Thieno[2,3-d]pyrimidine diones and their use in the treatment of reversible obstructive airways diseases

ABSTRACT

The invention provides pharmaceutically useful thieno[2,3-d]pyrimidinediones, processes for their production, pharmaceutical compositions containing them and methods of treatment involving their use.

This application is a continuation of application Ser. No. 09/117,426,filed on Jul. 30, 1998, now U.S. Pat. No. 6,180,635 which is a 371 ofPCT/SE98/00935 filed May 18, 1998.

This invention relates to pharmaceutically useful compounds, processesfor their production, pharmaceutical compositions containing them andmethods of treatment involving their use.

T-cells play an important role in the immune response, however inautoimmune disease T-cells are activated against particular tissues,e.g. causing the inflammation associated with rheumatoid arthritis.Interleukin-2 (IL-2) is an essential autocrine growth factor for T-cellsand hence inhibition of IL-2 transcription is beneficial in themodulation of autoimmune disease. Formation of a transcriptional complexof the protein nuclear factor of activated T-cells-1 (NFAT-1) on theIL-2 promoter is essential for IL-2 transcription. NFAT-1 mediatedtranscription has therefore been proposed as appropriate moleculartarget for immunomodulation, Y. Baine et al., J. Immunol., 1995, 154,3667-3677.

W. F. Michne et al., in J. Med. Chem. (1995) 38, 2557-2569 disclose anumber of quinazoline-2,4-diones and pyrrolo[3,4-d]pyrimidine-2,4-dioneswhich inhibit transcription regulated by the DNA region bound by theNFAT-1 protein.

We have now found novel thieno[2,3-d]pyrimidinediones which exhibitpharmacological activity, in particular immunosuppressive activity.

In a first aspect the invention therefore provides a compound of formula(I):

wherein:

R is —C(O)Ar¹, —C(R⁴)(R⁵)Ar¹, or Ar²;

Ar¹ is naphthyl, quinolyl, isoquinolyl, indolyl, benzofuranyl orbenzothienyl, each of which can be optionally substituted by one or moresubstituents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen ortrifluoromethyl, or Ar¹ is phenyl optionally substituted by one or moresubstituents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen,trifluoromethyl, amino, nitro, cyano, trifluoromethoxy, phenoxy,—CH₂N(R⁶)₂, —NHSO₂CF₃, C₁₋₄alkylsulphonylamino, —NHC(O)R^(6a), CO₂R⁷ or—C(O)NR⁸R^(8a);

R⁴represents H or C₁₋₄ alkyl;

R⁵represents H or OH;

each R⁶ independently represents H or C₁₋₄ alkyl, preferably methyl orethyl;

R^(6a) represents H, C₁₋₆ alkyl, aryl or arC₁₋₄alkyl, wherein the arylgroup or aryl moiety in the aralkyl group is phenyl or pyridyl, each ofwhich may be optionally substituted by one or more substituents selectedfrom C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylcarbonylamino, halogen ortrifluoromethyl;

R⁷ represents H or C₁₋₄ alkyl, preferably methyl or ethyl;

R⁸ and R^(8a) each independently represent H, C₁₋₄ alkyl, preferablymethyl or ethyl, phenyl or pyridyl;

Ar² is acenaphthenyl, indanyl, iminodihydrobenzofuranyl or fluorenyl,each of which can be optionally substituted by one or more substituentsselected from OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, or trifluoromethyl;

R¹ and R² are independently H, C₁₋₆ alkyl, C₃₋₆ alkenyl, CH₂C₃₋₅cycloalkyl or C₃₋₆ cycloalkyl;

R³ represents H, X—R⁹ or X—Ar³;

X represents S(O)_(n), C(O)NR¹⁰, C(O)O, NH(CO)NR¹⁰, NH(CO)O or SO₂NR¹⁰;

n is 0, 1 or 2;

R⁹ represents a methyl group optionally substituted by one or moresubstituents selected from CN, CO₂H, C₁₋₅ alkoxycarbonyl, 5-tetrazolyl,SO₂NH₂ or C(O)NR¹¹R¹², or R⁹ represents C₂₋₆ alkyl or C₃₋₆ alkenyl, eachof which may be optionally substituted by one or more substituentsselected from OH, CN, CO₂H, C₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl,5-tetrazolyl, azide, phthalimido, SO₂NH₂, C(O)NR¹¹R¹², NR¹³R¹⁴,NHC(O)R¹⁵ or NHSO₂R¹⁶ where R¹¹, R¹², R¹³ and R¹⁴ each independentlyrepresent H or C₁₋₄ alkyl,

R¹⁵ represents C₁₋₄ alkyl, C₁₋₄ alkoxy, di(C₁₋₄alkyl)amino, oralkoxyalkylene containing up to 6 carbon atoms, and R¹⁶ represents C₁₋₄alkyl or trifluoromethyl; or, additionally, in the case where Xrepresents C(O)NR¹⁰, NH(CO)NR¹⁰ or SO₂NR¹⁰, R⁹ and R¹⁰ together with thenitrogen atom to which they are attached may form a 4- to 7-memberedheterocyclic ring which may be optionally substituted by one or more OHgroups;

R¹⁰ represents H, C₁₋₆ alkyl or is linked to R⁹ as defined above; and

Ar³ is phenyl, pyridyl or pyridine N-oxide, each of which may beoptionally substituted by one or more substituents selected from OH,NO₂, NH₂, NHSO₂CF₃, C₁₋₄ alkoxy, bis-C₁₋₄alkanesulphonylanino,C₁₋₄alkylcarbonylamino or C₁₋₄alkoxycarbonylamino; or apharmaceutically-acceptable salt or solvate thereof.

In the present specification, unless otherwise indicated, an alkyl oralkenyl group or an alkyl or alkenyl moiety in a substituent group maybe linear or branched. Where a substituent in an alkenyl group is OH,phthalimido, NR¹³R¹⁴ or NHC(O)R¹⁵, the substituent is not attached to anunsaturated carbon atom. The alkyl moieties in a di(C₁₋₄ alkyl)aminogroup may be the same or different.

The group R is —C(O)Ar¹, —C(R⁴)(R⁵)Ar¹, or Ar².

The group R⁴ represents H or C₁₋₄ alkyl, preferably methyl or ethyl, andthe group represents H or OH.

Preferably Ar¹ is naphthyl, quinolyl, isoquinolyl, indolyl, benzofuranylor benzothienyl, each of which can be optionally substituted by one tofour, particularly one or two, substituents selected from C₁₋₄ alkyl(e.g. methyl or ethyl), C₁₋₄ alkoxy (e.g. methoxy or ethoxy), halogen(e.g. fluorine, chlorine or bromine) or trifluoromethyl, or Ar¹ isphenyl optionally substituted by one to four, particularly one or two,substituents selected from C₁₋₄ alkyl (e.g. methyl or ethyl), C₁₋₄alkoxy (e.g. methoxy or ethoxy), halogen (e.g. fluorine, chlorine orbromine), trifluoromethyl, amino, nitro, cyano, trifluoromethoxy,phenoxy, —CH₂N(R⁶)₂, —NHSO₂CF₃, C₁₋₄alkylsulphonylamino, —NHC(O)R^(6a),CO₂R⁷ or —C(O)NR⁸R^(8a).

Most preferably Ar¹ is naphthyl, quinolyl or benzofuranyl, or a phenylgroup optionally substituted by one or two substituents selected fromC₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, trifluoromethyl, nitro, amino, cyano,phenoxy or —NHC(O)R^(6a).

The group Ar² is preferably acenaphthenyl, indanyl,iminodihydrobenzofuranyl or fluorenyl, each of which can be optionallysubstituted by one to four, particularly one or two, substituentsselected from OH, C₁₋₄ alkyl (e.g. methyl or ethyl), C₁₋₄ alkoxy (e.g.methoxy or ethoxy), halogen (e.g. fluorine, chlorine or bromine) ortrifluoromethyl. Especially preferred are indanyl,iminodihydrobenzofuranyl and hydroxy-substituted indanyl groups.

R^(6a) is preferably H, C₁₋₆, particularly C₁₋₄, alkyl, aryl orarC₁₋₄alkyl, wherein the aryl group or aryl moiety in the aralkyl groupis phenyl or pyridyl, each of which may be optionally substituted by oneto four, especially one or two, substituents selected from C₁₋₄ alkyl(e.g. methyl or ethyl), C₁₋₄ alkoxy (e.g. methoxy or ethoxy), C₁₋₄alkylcarbonylamino (e.g. methyl- or ethylcarbonylamino), halogen (e.g.fluorine, chlorine or bromine) or trifluoromethyl.

Most preferably, R^(6a) represents a phenyl or phenylC₁₋₄alkyl groupsubstituted in the aromatic ring by one or two substituents selectedfrom methoxy and methylcarbonylamino.

Preferably R¹ and R² are independently H, C₁₋₄ alkyl, C₃₋₄ alkenyl orC₃₋₆ cycloalkyl.

It is preferred that R¹ is C₃₋₄ alkyl or C₄ alkenyl, in particular1-methylethyl, 2-methylpropyl or 2-methylpropenyl.

It is preferred that R² is H or, especially, methyl.

R³ represents H, X—R⁹ or X—Ar³.

X represents S(O)_(n) where n is 0, 1 or 2, C(O)NR¹⁰, C(O)O, NH(CO)NR¹⁰,NH(CO)O or SO₂NR¹⁰.

Preferably R⁹ represents a methyl group optionally substituted by CN,CO₂H, C₁₋₅ alkoxycarbonyl, 5-tetrazolyl, SO₂NH₂ or C(O)NR¹¹R¹², or R⁹preferably represents C₂₋₆ alkyl or C₃₋₆ alkenyl, each of which may beoptionally substituted by one to four, particularly one or two,substituents selected from OH, CN, CO₂H, C₁₋₅ alkoxy, C₁₋₅alkoxycarbonyl, 5-tetrazolyl, azide, phthalimido, SO₂NH₂, C(O)NR¹¹R¹²,NR¹³R¹⁴, NHC(O)R¹⁵ or NHSO₂R¹⁶ where R¹¹, R¹², R¹³ and R¹⁴ eachindependently represent H or C₁₋₄ alkyl, particularly methyl or ethyl,R¹⁵ represents C₁₋₄ alkyl, particularly methyl or ethyl, C₁₋₄ alkoxy,particularly methoxy or ethoxy, di(C₁₋₄alkyl)amino, particularlydimethylamino or diethylamino, or alkoxyalkylene containing from 2 to 4carbon atoms, and R¹⁶ represents C₁₋₄ alkyl, preferably methyl or ethyl,or trifluoromethyl; or, additionally, in the case where X representsC(O)NR¹⁰, NH(CO)NR¹⁰ or SO₂NR¹⁰, R⁹ and R¹⁰ together with the nitroenatom to which they are attached may form a 5- or 6-membered heterocyclicring which may be optionally substituted by one or two OH groups.

More preferably R⁹ represents a methyl group optionally substituted byCO₂H or C(O)NR¹¹R¹², or a C₂₋₄ alkyl group (e.g. ethyl, propyl or butyl)which may be optionally substituted by one or two substituents selectedfrom OH, CO₂H, C₁₋₅ alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl), azide, phthalimido, NR¹³R¹⁴, NHC(O)R¹⁵ or NHSO₂R¹⁶; orR⁹ and R¹⁰ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclic ring which may be optionallysubstituted by an OH group.

Preferably, R¹⁰ represents H, C₁₋₂ alkyl, especially methyl, or islinked to R⁹ as defined above.

Most preferably, each of R¹¹, R¹², R¹³ and R¹⁴ represents hydrogen.

Most preferably, R¹⁵ represents methyl, methoxy, dimethylamino ormethoxymethylene.

Most preferably, R¹⁶ represents methyl or trifluoromethyl.

Preferably, Ar³ is phenyl, pyridyl or pyridine N-oxide, each of whichmay be optionally substituted by one to four, particularly one or two,substituents selected from OH, NO₂, NH₂, NHSO₂CF₃, C₁₋₄ alkoxy(particularly methoxy or ethoxy), bis-C₁₋₄alkanesulphonylamino(particularly bis-C₂₋₄ alkanesulphonylamino), C₁₋₄alkylcarbonylamino(particularly C₁₋₂alkylcarbonylamino) or C₁₋₄alkoxycarbonylamino(particularly C₁₋₂alkoxycarbonylamino).

The group Ar³ is very preferably phenyl, pyridyl or pyridine N-oxide,each of which may be optionally substituted by one or two substituentsselected from OH, NO₂, NH₂, methoxy, bis-methanesulphonylamino,methylcarbonylamino or methoxycarbonylamino.

Particularly preferred compounds of the invention include:

6-(4-Methoxyphenylmethyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(4-Methoxyphenylmethyl)-3-methyl-1-(2-methyl-2-propenyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione,

1-(2-Methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(2-pyridinyl)-thio]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

5-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

Methyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]butanoate,

4-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]butanoicacid,

Methyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)sulfinyl]butanoate,

Methyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)sulfonyl]butanoate,

4-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)sulfonyl]butanoicacid,

6-Benzyl-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(1-methylethyl)-6-(phenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1-Hydroxy-1-phenyl)methyl]-3-methyl-1-(2-methylpropl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(±)5-[(2-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylnethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide,

(3R)-1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylnethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl}pyrrolidin-3-ol,

1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl}piperidin-4-ol,

(3R)-1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl}piperidin-3-ol,

1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-3,N-dimethyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide,

2-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carboxamido}aceticacid,

3-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carboxamido}propanoicacid,

2-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carboxamido}acetamide,

1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl}pyrrolidine,

1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-sulfonamide,

5-[(3-Methoxyphenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

5-[(3-Hydroxyphenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

5-[(3-Hydroxyphenyl)sulfinyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

5-[(3-Hydroxyphenyl)sulfonyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

3-Methyl-1-(2-methylpropy)-6-(1-naphthalenylmethyl)-5-[(3-nitrophenyl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

5-[(3-Aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

5-{[3-{(Bis-methanesulfonyl)amino}phenyl]thio}-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

5-[(3-Methoxycarbonylaminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

5-[(3-Acetamidophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(4-nitrophenyl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

5-[(4-Aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(5-nitropyridin-2-yl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

2-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]thio}pyridineN-oxide,

5-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

5-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}acetamide,

N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}-N′,N′-dimethylurea,

N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}-methoxyacetamide,

MethylN-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}carbamate,

N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}methanesulfonamide,

N-{(3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}trifluoromethanesulfonamide,

5-{[3-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]thio}-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

N-(2-Hydroxyethyl)-N′-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)]urea,

2-Hydroxyethyl[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbamate,

N-(2-Hydroxyethyl)-N-methyl-N′-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)]urea,

6-[(1-Hydroxy-1-(3-fluorophenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

6-[(3-Fluorophenyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

6-[(1-Hydroxy-1-(2-bromophenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1-Hydroxy-1-(2-methylphenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1-Hydroxy-1-(3-cyanophenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1-Hydroxy-1-(3-trifluoromethylphenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1-Hydroxy-1-(3-phenyloxyphenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1-Hydroxy-1-(1-naphthalenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1-Hydroxy-1-(6-quinolinyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1-Hydroxy-1-(4-quinolinyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(±)6-[1-(Benzo[b]furan-2-yl)-1-hydroxymethyl]-3-methyl-1-(2-methylpropyl))thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1-Hydroxy-1-(2-chloro-6-fluorophenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno-[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1-Hydroxy-1-phenyl)ethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1-Hydroxy-1-(4-trifluoromethylphenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(±)6-(2,3-dihydro-1-hydroxy-1H-indenyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1-Hydroxy-1-(2-quinolinyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(1-Hydroxy-1-[3-quinolinyl]methyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(2-bromophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(2-methylphenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(3-cyanophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(3-trifluoromethylphenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(3-phenyloxyphenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-(6-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-(2-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,trifluoroacetic acid salt,

6-(2-Benzo[b]furanylmethyl)-3-methyl-1-(2-methylpropyl)-)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(2-Chloro-6-fluorophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(1-Phenylethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H) -dione,

6-(4-Trifluoromethylphenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(±)6-(2,3-dihydro-1H-inden-1-yl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(3-Imino-1,3-dihydro-benzo[c]furan-1-yl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

2-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl)methyl]benzamide,

(±)6-(1-Hydroxy-1-[1-naphthalenyl]methyl)-5-([3-hydroxypropyl]thio)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(±)-5-[(3-Hydroxybutyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(3-Fluorophenyl)methyl-5-[(3-hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

5-[(5-Amino-2-pyridinyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

Ethyl1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate,

1,2,3,4-Tetrahydro-3,N,N-trimethyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide,

6-[1-Hydroxy-(4-nitrophenyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione,

6-(4-Nitrophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione,

6-(4-Aminophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,

4-(3,4-Dimethoxyphenyl)-N-{4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl)methyl]phenyl}-butanamide,and

3-Acetamido-N-(4-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl)methyl]phenyl)benzamide.

According to the invention there is also provided a process for thepreparation of a compound of formula (I) which comprises:

(a) preparation of a compound of formula (I) wherein X is SO₂, byoxidation of a compound of formula (I) wherein X is S(O)_(n) and n is 0or 1, in the presence of an appropriate oxidising agent (e.g.3-chloroperoxybenzoic acid) and an appropriate solvent (e.g.dichloromethane) for example at 0° C. to ambient temperature (20° C.);or

(b) preparation of a compound of formula (I) wherein X is SO, byoxidation of a compound of formula (I) wherein X is S, in the presenceof an appropriate quantity of a suitable oxidising agent (e.g. potassiumperoxymonosulphate, commercially sold under the trade mark “OXONE”) in asuitable solvent (e.g. aqueous methanol), for example, at ambienttemperature; or

(c) preparation of a compound of a formula (I) wherein X is S, byreacting a compound of general formula

wherein R, R¹ and R² are as hereinbefore defined, with a compound ofgeneral formula (III), R¹⁷—S—S—R¹⁷, wherein the groups R¹⁷ bothrepresent R⁹ or Ar³ as previously defined, or with a compound of generalformula (IV), L—S—R¹⁷, wherein L represents a leaving group such as anarylsulphinate group and R¹⁷ is as defined above, in the presence oflithium diisopropylamide at a temperature from −78° C. to 50° C.; or

(d) preparation of a compound of formula (I) wherein R³ represents H, byreaction of a compound of general formula

wherein R¹⁸ and R¹⁹ each independently represent an alkyl (e.g. ethyl)or aryl group and R and R¹ are as hereinbefore defined, with a compoundof general formula (VI), R²NH₂, wherein R² is as hereinbefore defined,in the presence of a suitable solvent (e.g. ethanol), for example, atelevated temperature and pressure; or

(e) preparation of a compound of formula (I) wherein X is C(O)NR¹⁰, byreacting a compound of general formula

wherein R, R¹ and R² are as hereinbefore defined, with a compound ofgeneral formula

wherein R⁹ and R¹⁰ are as hereinbefore defined, in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazolehydrate;

(f) preparation of a compound of formula (I) wherein X is NH(CO)NR¹⁰, byreacting a compound of general formula

wherein R, R¹ and R² are as hereinbefore defined, with a compound offormula (VI) as described above, in the presence of a solvent such astoluene; or

(g) preparation of a compound of formula (I) wherein X is NH(CO)O, byreacting a compound of formula (IX) as defined above, with a compound ofgeneral formula (X), R⁹OH, wherein R⁹ is as hereinbefore defined, in thepresence of a solvent such as toluene; or

(h) preparation of a compound of formula (I) wherein X is SO₂NR¹⁰, byreacting a compound of general formula

wherein L¹ represents a leaving group such as a halogen atom (e.g.chlorine) and R, R¹ and R² are as hereinbefore defined, with a compoundof formula (VIII) as defined above, in the presence of a solvent such asdichloromethane; or

(i) preparation of a compound of formula (I) wherein X is C(O)O, byreacting a compound of general formula

wherein R^(3′) represents CO₂R⁹ or CO₂Ar³ and R, R¹, R¹⁸ and R¹⁹ are ashereinbefore defined, with a compound of general formula (VI) ashereinbefore defined, in the presence of a suitable solvent (e.g.ethanol), for example, at elevated temperature and pressure;

and optionally after (a), (b), (c), (d), (e), (f), (g), (h) or (i)converting the compound of formula (I) obtained to a further compound offormula (I) and/or forming a pharmaceutically-acceptable salt or solvatethereof.

Compounds of formula (II) in which R is —C(═O)Ar¹ may conveniently beprepared by reacting a compound of general formula

in which R¹ and R² are as hereinbefore defined, with a compound ofgeneral formula (XIII), Ar¹COCl, in the presence of aluminium (E)chloride and a solvent such as 1,2-dichloroethane under refluxconditions; or, alternatively, by oxidising a compound of generalformula

in which R⁴ represents H, R⁵ represents OH and R¹ and R² are aspreviously defined, in the presence of potassium permanganate and1,4,7,10,13,16-hexaoxacyclooctadecane (commercially sold as“18-Crown-6”) in a solvent such as dichloromethane at ambienttemperature.

Compounds of formula (XIV) in which R⁵ is OH and R¹, R², R⁴ and Ar¹ areas hereinbefore defined may be prepared by reacting a compound offormula (XII) as defined above with a to compound of general formula

in which R⁴ is as hereinbefore defined in the presence of lithiumdiisopropylamide at a temperature from −78° C. to 50° C.

Compounds of formula (XIV) in which R⁵ is H and R¹, R², R⁴ and Ar¹ areas hereinbefore defined may be readily prepared by reducing acorresponding compound of formula (XIV) in which R⁵ is OH in thepresence of triethylsilane and trifluoroacetic acid at ambienttemperature.

Compounds of formula (II) in which R is Ar² can be prepared by reactinga compound of formula (XII) as hereinbefore defined with 1-indanone,2-indanone, 9-fluoreneone or 1-acenapthenone in the presence of lithiumdiisopropylamide and optionally cerium (E) chloride at −78° C. to 50° C.temperature, followed by a reduction reaction, e.g. in the presence oftriethylsilane and trifluoroacetic acid.

Compounds of formula (V) may conveniently be prepared by reacting acompound of general formula

wherein R, R¹ and R¹⁸ are as hereinbefore defined, with a compound ofgeneral formula

wherein R¹⁹ is as hereinbefore defined and Hal is a halogen atom (e.g.chlorine), in the presence of a suitable base (e.g. triethylamine) and asolvent such as dichloromethane.

Compounds of formula (XVI) in which R¹ is H may be prepared by reactinga compound of general formula (XVEm), R—CH₂CHO, wherein R is aspreviously defined, with a compound of general formula

wherein R¹⁸ is as previously defined, and with elemental sulfur, in asuitable solvent, e.g. dimethylformamide.

Compounds of formula (XVI) in which R¹ is CH₂C₁₋₅ alkyl, CH₂C₂₋₅ alkenylor CH₂C₃₋₅cycloalkyl may suitably be prepared by reacting acorresponding compound of formula (XVI) in which R¹ is H, with acompound of general formula (XX), R²⁰CO₂H, wherein R²⁰ represents C₁₋₅alkyl, C₂₋₅ alkenyl or C₃₋₅ cycloalkyl, and with a reducing agent suchas sodium borohydride, in the absence of a solvent.

Compounds of formula (XVI) in which R¹ is C₁₋₆ alkyl or C₃₋₆ cycloalkylmay conveniently be prepared by reacting a corresponding compound offormula (XVI) in which R¹ is H, in the presence of a solvent such astoluene and catalytic toluenesulphonic acid under reflux conditions,with a compound of general formula

wherein the groups R²¹ are both methyl or ethyl groups, and R²² and R²³each independently represent a hydrogen atom or an alkyl group ortogether form a hydrocarbyl ring, the total number of carbon atoms inR²² and R²³ taken together not exceeding five, followed by reaction witha reducing agent such as sodium borohydride.

Compounds of formula (Va) may be prepared in a similar manner to thecompounds of formula (V) but using in place of the compound of formula(XVI), a compound of general formula

in which R, R¹, R^(3′) and R¹⁸ are as previously defined.

Compounds of formula (XXII) in which R¹ is H may be prepared by reactinga compound of general formula (XXIII), RCH₂C(O)R^(3′), wherein R andR^(3′) are as previously defined, with a compound of formula (XIX) ashereinbefore defined and also with elemental sulfur in a suitablesolvent.

Compounds of formula (XXII) in which R¹ is other than hydrogen may beprepared by processes analogous to those described above for thepreparation of compounds of formula (XVI) in which R¹ is other thanhydrogen.

Compounds of formula (VII) may suitably be prepared by reacting acompound of formula (II) above with carbon dioxide in the presence oflithium diisopropylamide, e.g. in tetrahydrofuran at a temperature from−78° C. to 50° C. under pressure.

Compounds of formula (IX) may be easily prepared by reacting a compoundof formula (VII) as described above with diphenylphosphoryl azide,(C₆H₅O)₂P(O)N₃, in the presence of a solvent, e.g. a mixture oftriethylamine and toluene.

Compounds of formula (XI) in which L¹ represents a halogen atom such aschlorine can be prepared by reacting a compound of formula (II) asdefined above with lithium diisopropylamide and sulfur dioxide to forman intermediate which is then further reacted with N-chlorosuccinimideand aqueous hydrochloric acid, in the presence of a solvent such asdichloromethane.

Compounds of formula (I) can be converted into further compounds offormula (I) using standard procedures. For example, compounds of formula(I) where Ar³ is nitrophenyl can be converted to compounds of formula(I) where Ar³ is aminophenyl by reduction using iron powder and ammoniumchloride in ethanol under reflux conditions; or compounds of formula (I)where Ar³ is pyridyl can be converted to compounds of formula (I) whereAr³ is pyridine N-oxide by reaction with 3-chloroperoxybenzoic acid in asolvent such as dichloromethane.

Compounds of formula (III), (IV), (VI), (VII), (X), (XII), (XIII), (XV),(XVII), (XVIII), (XIX), (XX), (XXI) and (XXIII) are either commerciallyavailable, are well known in the literature or may be prepared easilyusing known techniques.

It will be appreciated by those skilled in the art that in the processesdescribed above the functional groups (e.g. hydroxy, amino or carboxylgroups) of intermediate compounds may need to be protected by protectinggroups. The final stage in the preparation of the compounds of theinvention may involve the removal of one or more protecting groups. Theprotection and deprotection of functional groups is fully described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1991).

The compounds of formula (I) above may be converted to apharmaceutically-acceptable salt or solvate thereof, preferably an acidaddition salt such as a hydrochloride, hydrobromide, phosphate, acetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate, or an alkali metal salt such as a sodium orpotassium salt.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention.

Isomers may be resolved or separated by conventional techniques, e.g.chromatography or fractional crystallisation. Enantiomers may beisolated by separation of a racemic or other mixture of the compoundsusing conventional techniques (e.g. chiral HPLC). Alternatively thedesired optical isomers may be made by reaction of the appropriateoptically active starting materials under conditions which will notcause racemisation, or by derivatisation, for example with a homochiralacid followed by separation of the diastereomeric derivatives byconventional means (e.g. HPLC, chromatography over silica) or may bemade with achiral starting materials and chiral reagents. Allstereoisomers are included within the scope of the invention.

The compounds of the invention may be isolated from their reactionmixtures using conventional techniques.

The compounds of the invention are useful because they possesspharmacological activity in human and non-human animals. They aretherefore indicated as pharmaceuticals for use in the (prophylactic)treatment of autoimmune, inflammatory, proliferative andhyperproliferative diseases and immunologically-mediated diseasesincluding rejection of transplanted organs or tissues and AcquiredImmunodeficiency Syndrome (AIDS). Examples of these conditions are:

(1) (the respiratory tract) reversible obstructive airways diseasesincluding asthma, such as bronchial, allergic, intrinsic, extrinsic anddust asthma, particularly chronic or inveterate asthma (e.g. late asthmaand airways hyper-responsiveness); bronchitis; acute, allergic, atrophicrhinitis and chronic rhinitis including rhinitis caseosa, hypertrophicrhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa;membranous rhinitis including croupous, fibrinous and pseudomembranousrhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitisnervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lungand related diseases, fibroid lung and idiopathic interstitialpneumonia;

(2) (bone and joints) rheumatoid arthritis, seronegativespondyloarthropathies (including ankylosing spondylitis, psoriaticarthritis and Reiter's disease), Behcet's disease, Sjogren's syndromeand systemic sclerosis;

(3) (skin) psoriasis, atopical dermatitis, contact dermatitis and othereczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus,bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas,vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopeciaareata and vernal conjunctivitis;

(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilicgastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis,food-related allergies which have effects remote from the gut, e.g.,migraine, rhinitis and eczema;

(5) (other tissues and systemic disease) multiple sclerosis,atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupuserythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis,myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophiliafascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome andidiopathic thrombocytopenia pupura;

(6) (allograft rejection) acute and chronic following, for example,transplantation of kidney, heart, liver, lung, bone marrow, skin andcornea; and chronic graft versus host disease.

The compounds of the invention are also indicated for use asantimicrobial agents, and thus may be used in the treatment of diseasescaused by pathogenic micro-organisms.

Accordingly, the present invention provides a compound of formula (I),or a pharmaceutically-acceptable salt or solvate thereof, ashereinbefore defined for use in therapy.

In another aspect, the invention provides the use of a compound offormula (I), or a pharmaceutically-acceptable salt or solvate thereof,as hereinbefore defined in the manufacture of a medicament for use intherapy.

The invention further provides a method of effecting immunosuppressionwhich comprises administering to a patient a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically-acceptablesalt or solvate thereof, as hereinbefore defined.

The invention still further provides a method of treating, or reducingthe risk of, a reversible obstructive airways disease in a patientsuffering from, or at risk of, said disease, which comprisesadministering to the patient a therapeutically effective amount of acompound of formula (I), or a pharmaceutically-acceptable salt orsolvate thereof, as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated.

The compounds of formula (I) and pharmaceutically-acceptable salts andsolvates thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically-acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99%w (per cent by weight), morepreferably less than 80%w, e.g. from 0.10 to 70%w, and even morepreferably less than 50%w, of active ingredient, all percentages byweight being based on total composition.

Thus, the present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically-acceptablesalt or solvate thereof, as hereinbefore defined, in association with apharmaceutically-acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically-acceptable salt orsolvate thereof, as hereinbefore defined, with apharmaceutically-acceptable adjuvant, diluent or carrier.

The pharmaceutical composition of the invention may be administeredtopically (e.g. to the lung and/or airways or to the skin) in the formof solutions, suspensions, heptafluoroalkane aerosols and dry powderformulations; or systemically, e.g. by oral administration in the formof tablets, capsules, syrups, powders or granules, or by parenteraladministration in the form of solutions or suspensions, or bysubcutaneous administration or by rectal administration in the form ofsuppositories or transdermally.

The invention will be illustrated by the subsequent examples in whichthe following abbreviations are used: m.p.=melting point, NMR=nuclearmagnetic resonance, MS=mass spectrometry and h=hour(s).

EXAMPLE 16-(4-Methoxyphenylmethyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

a) 3-(4-Methoxyphenyl)propanal

A solution of 3-(4-methoxyphenyl)propan-1-ol (15.02 g) indichloromethane (100 ml) was added to a stirred suspension of pyridiniumchlorochromate (29 g) in dichloromethane (250 ml). The mixture wasstirred for 2 hours then filtered through a kieselguhr pad. The residuewas washed with ether (3×500 ml) and the combined liquors wereevaporated under reduced pressure. The residual oil was purified byvacuum distillation to give the subtitle compound (6.81 g) as an oil.

MS (EI) 164 (M⁺), 121 (BP)

¹H NMR (CDCl₃) δ2.75 (2H, t); 2.91 (2H, t); 3.79 (3H, s); 6.84 (2H, d);7.12 (2H, d); 9.81 (1H, s).

b) Ethyl 2-amino-5-(4-methoxyphenylmethyl)-3-thiophenecarboxylate

3-(4-Methoxyphenyl)propanal (5.17 g) was added portionwise over 20minutes to a stirred solution of ethyl cyanoacetate (3.4 g), sulfur(0.975 g) and triethylamine (3.00 ml) in dimethylformamide (10 ml).After a further 3 hours, the mixture was diluted with water (400 ml) andextracted with ethyl acetate (2×250 ml). The organic extracts were driedover anhydrous magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography over silicaeluting with ethyl acetate:petroleum ether (1:3) to give the subtitlecompound (7.08 g).

MS (EI) 291 (M⁺)

¹H NMR (CDCl₃) δ1.33 (3H, t); 3.79 (3H, s); 3.85 (2H, s); 4.24 (2H, q);5.79 (2H, s, br); 6.68 (1H, s); 6.84 (2H, d); 7.13 (2H, d).

c) N-[3-Ethoxycarbonyl-5-(4-methoxyphenylmethyl)-2-thienyl]-O-ethylcarbamate

Ethyl chloroformate (1.00 ml) was added to a stirred solution of ethyl2-amino-5-(4-methoxyphenylmethyl)-3-thiophenecarboxylate (3.00 g) andpyridine (4.00 ml) in dichloromethane (30 ml) at 0-5° C. After 45minutes, the mixture was washed with hydrochloric acid (10%, 50 ml). Theaqueous phase was extracted with further dichloromethane (30 ml).Combined organic extracts were dried over anhydrous magnesium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby column chromatography over silica eluting withethanol:dichloromethane gradient elution (1:19 to 1:3) to give thesubtitle compound (5.61 g).

¹H NMR (CDCl₃) δ1.29-1.37 (6H, m); 3.79 (3H, s); 3.95 (2H, s); 4.22-4.32(4H, m); 6.82-6.85 (3H, m); 7.15 (2H, d); 10.13 (1H, s, br).

d)6-(4-Methoxyphenylmethyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

Methylamine (8 ml) was condensed into a cooled solution ofN-[3-ethoxycarbonyl-5-(4-methoxyphenylmethyl)-2-thienyl]-O-ethylcarbamate (0.93 g) in ethanol (15 ml). The resulting solution was heatedat 120° C. in a sealed bomb for 16 hours. The solvent was evaporatedunder reduced pressure and the residue was triturated with ether to givethe title compound (0.31 g) as a solid.

MS (EI) 291 (M⁺)

¹H NMR (DMSO-D₆) δ3.17 (3H, s); 3.73 (3H, s); 4.01 (2H, s); 6.87-6.91(3H, m); 7.19 (2H, d); 12.10 (1H, s, br).

EXAMPLE 26-(4-Methoxyphenylmethyl)-3-methyl-1-(2-methyl-2-propenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

1-Bromo-2-methyl-2-propene (0.055ml) was added to a stirred suspensionof potassium carbonate (0.203 g) and6-(4-methoxyphenylmethyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(0.15 g) in acetone (5 ml). After 16 h at room temperature, the mixturewas diluted with saturated aqueous sodium chloride solution andextracted with ethyl acetate. The organic extracts were dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified by column chromatography over silica,eluting with ethyl acetate:petroleum ether (1:3 then 3:7 then 7:13) togive the title compound (0.11 g).

m.p. 111° C.

MS (EI) 356 (M+)

¹H NMR (CDCl₃) δ1.75 (3H, s); 3.43 (3H, s); 3.81 (3H, s); 4.00 (2H, s);4.48 (2H, s); 4.83 (1H, s); 4.98 (1H, s); 6.86 (2H, d); 7.02 (1H, s);7.14 (2H, d).

EXAMPLE 31-(2-Methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

a) 3-(1-naphthyl)propanoic acid

10% Palladium on carbon (1.00 g) was added to a suspension of3-(1-naphthyl)acrylic acid (50.0 g) in tetrahydrofuran (500 ml). Themixture was hydrogenated at 6 atmospheres for 18 hours then filteredthrough a kieselguhr pad washing with ethyl acetate (3×100 ml). Thefiltrate was evaporated under reduced pressure to give the subtitlecompound (50.0 g) as a solid.

1H NMR (DMSO-D₆) δ2.65 (2H, t); 3.30 (2H, t); 7.37-7.46 (2H, m);7.49-7.60 (2H, m); 7.79 (1H, d); 7.93 (1H, d); 8.07 (1H, d); 12.10 (1H,s, br).

b) Ethyl 2-amino-5-(1-naphthalenylmethyl)-3-thiophenecarboxylate

A solution of oxalyl chloride (7.40 ml) in anhydrous dichloromethane (50ml) was added dropwise to a stirred suspension of3-(1-naphthyl)propanoic acid (8.50 g) in anhydrous dichloromethane (100ml) and dimethylformamide (0.1 ml). After a further 2 hours, theresulting solution was evaporated under reduced pressure and theresidual oil dried in vacuo at 50° C. for 4 hours.

The oil was redissolved in anhydrous tetrahydrofuran (45 ml) and addedto a mixture of 10% palladium on carbon (0.50 g) and anhydrous2,6-lutidine (5.82 ml) in anhydrous tetrahydrofuran (30 ml). The mixturewas hydrogenated at 2 atmospheres for 4 days and then filtered through akieselguhr pad. The filtrate was evaporated under reduced pressure andthe residual oil dried in vacuo to give a solid.

This solid was redissolved in anhydrous dimethylformamide (20 ml). Ethylcyanoacetate (4.53 ml) and sulfur (1.36 ml) were added and the mixturestirred at 50° C., under nitrogen for 2 hours. Water (300 ml) followedby saturated sodium chloride solution (50 ml) were added and the mixturewas extracted with ether (3×300 ml). The combined organic extracts weredried over anhydrous magnesium sulfate, filtered and evaporated underreduced pressure. The residue was purified by column chromatography oversilica, eluting with ether:hexane (2:3) to give the subtitle compound(11.00 g).

MS (APCI) 312.1 ((M+H)⁺),

¹HMR (DMSO-D₆) δ1.20 (3H, t); 4.12 (2H, q); 4.35 (2H, s); 6.56 (1H, s);7.08 (2H, s, br); 7.41-7.56 (4H, m); 7.84 (1H, d); 7.90-7.96 (1H, m);8.09-8.13 (1H, m).

c) Ethyl2-(2-methylpropyl)amino-5-(1-naphthalenylmethyl)-3-thiophenecarboxylate

Sodium borohydride (1.3 g) was added in 10 portions over 5 hours to astirred solution of ethyl2-amino-5-(1-naphthalenylmethyl)-3-thiophenecarboxylate (5.50 g) in2-methylpropanoic acid (40 ml) at 0° C. The mixture was stirred at roomtemperature for 16 hours then further sodium borohydride (1.8 g) wasadded in 10 portions over 8 hours and stirring continued for a further16 hours. The solution was poured into water (1000 ml), neutralized withsodium bicarbonate and extracted with ethyl acetate (2×500 ml). Theorganic extracts were dried over anhydrous magnesium sulfate, filteredand evaporated under reduced pressure. The residue was purified bycolumn chromatography over silica, eluting with ether:hexane (1:3) togive the subtitle compound (6.20 g).

m.p. 57-59° C.

MS (APCI) 368.1 ((M+H)⁺),

¹H NMR (DMSO-D₆) δ0.86 (6H, d); 1.22 (3H, t); 1.66-1.92 (1H, m); 2.91(2H, dd); 4.14 (2H, q); 4.40 (2H, s); 6.70 (1H, s); 7.43-7.57 (4H, m);7.84 (1H, dd); 7.92-7.95 (1H,m); 8.11-8.14 (1H, m).

d)N′-Acetyl-N-(2-methylpropyl)-N-[3-ethoxycarbonyl-5-(1-naphthalenylmethyl)-2-thienyl]urea

Acetyl chloride (1.08 ml) was added to a stirred suspension of silvercyanate (2.37 g) in anhydrous toluene (50 ml). After 1 hour, ethyl2-(2-methylpropyl)amino-5-(1-naphthalenylmethyl)-3-thiophenecarboxylate(4.646 g) was added and stirring was continued for 16 hours. The mixturewas filtered and the solid residue was washed with ether (50 ml). Thecombined liquors were evaporated under reduced pressure and the residuepurified by column chromatography over silica, eluting with ether:hexane(1:1) to give the subtitle compound (5.05 g) as an oil.

MS (APCI) 453.1 ((M+H)⁺),

¹H NMR (CDCl₃) δ0.87 (6H, d); 1.29 (3H, t); 1.78-1.92 (1H, m); 2.44 (3H,s); 3.06-3.80 (2H, br); 4.24 (2H, q); 4.53 (2H, s); 7.09 (1H, s); 7.30(1H, s, br); 7.41-7.58 (4H,m); 7.84 (1H, d); 7.90 (1H, dd); 7.99 (1H,dd).

e)1-(2-Methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

Sodium ethoxide (0.036 g) was added to a solution ofN′-acetyl-N-(2-methylpropyl)-N-[3-ethoxycarbonyl-5-(1-naphthalenylmethyl)-2-thienyl]urea(0.20 g) in ethanol (4 ml). The mixture was stirred for 3 hours thenfurther sodium ethoxide (0.036 g) was added. After a further 3 hours,the mixture was poured into hydrochloric acid (2M, 20 ml) and extractedwith ethyl acetate (2×20 ml). The organic extracts were dried overanhydrous magnesium sulfate, filtered and evaporated under reducedpressure. The residua l solid was recrystallised from ethylacetate/hexane to give the title compound (0.105 g).

m.p. 189-190° C.

MS (APCI) 365.1 ((M+H)⁺),

¹H NMR (DMSO-D₆) δ0.84 (6H, d); 2.02-2.18 (1H, m); 3.57 (2H, d); 4.60(2H, s); 7.01 (1H, s); 7.48-7.59 (4H, m); 7.87 (1H, dd); 7.95 (1H, dd);8.16 (1H, dd); 11.34 (1H, s, br).

EXAMPLE 43-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyridine-2,4(1H,3H)-dione)

Sodium ethoxide (0.18 g) was added to a stirred solution ofN′-acetyl-N-(2-methylpropyl)-N-[3-ethoxycarbonyl-5-(1-naphthalenylmethyl)-2-thienyl]urea(Example 3, step c), 0.30 g) in ethanol (6 ml). After 6 hours,iodomethane (0.165 ml) was added. After a further 16 hours iodomethane(0.165 ml) was added, After a further 24 hours, the reaction mixture waspoured onto hydrochloric acid (2M, 30 ml) and extracted with ethylacetate (2×30 ml). The organic extracts were dried over anhydrousmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography over silica, eluting, withether:hexane (1:1) and then triturated with ether to give the titlecompound (0.24 g,).

m.p. 137-138° C.

MS (APCI) 379.1 ((M+H)⁺),

¹H NMR (CDCl₃) δ0.93 (6H, d); 2.18-2.32 (1H, m); 3.38 (3H, s); 3.68 (2H,d); 4.52 (2H, s); 7.04 (1H, t); 7.40-7.52 (4H, m); 7.82 (1H, d);7.86-7.90 (1H, m); 7.95-8.02 (1H, m).

EXAMPLE 53-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(2-pyridinyl)thio]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

n-Butyllithium (2.0M solution in hexanes, 0.32 ml) was added dropwise toa solution of diisopropylamine (0.093 ml) in anhydrous tetrahydrofuran(5 ml) at 0° C., under nitrogen. The solution was stirred for 5 minutesthen cooled to −78° C. and a solution of3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(0.20 g) in anhydrous tetrahydrofuran (5 ml) was added. After 15minutes, a solution of 2,2′-dipyridyl disulfide (0.145 g) in anhydroustetrahydrofuran (2 ml) was added The mixture was stirred for a further 1hour at −78° C. then allowed to warm to room temperature. The reactionmixture was poured onto saturated aqueous sodium bicarbonate solution(30 ml) and then extracted with ether (2×30 ml). The organic extractswere dried over anhydrous magnesium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by columnchromatography over silica, eluting with acetone:hexane (1:2) and wasthen recrystallised from ethyl acetate/hexane to give the title compound(0.172 g).

m.p. 148-149° C.

MS (APCI) 488.1 ((M+H)⁺),

¹H NMR (CDCl₃) δ0.89 (6H, d); 2.10-2.25 (1H, m); 3.31 (3H, s); 3.63 (2H,d); 4.73 (2H, s); 7.05 (1H, dd); 7.17 (1H, d); 7.36 (1H, td); 7.40-7.58(4H, m); 7.81 (1H, dd); 7.85 (1H, d); 7.98 (1H, d); 8.42-8.45 (1H, m).

EXAMPLE 65-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

Prepared according to the procedure described in Example 5 fromn-butyllithium (2.0M solution in hexanes, 0.32 ml) and diisopropylamine(0.093 ml) in anhydrous tetrahydrofuran (5 ml),3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(0.20 g) in anhydrous tetrahydrofuran (5 ml)and3-{[dimethyl(1,1-dimethylethyl)silyl]oxy}propyl4-methylphenylthiosulfonate (0.19 g, J. Med. Chem. 1995, 38, 2557) inanhydrous tetrahydrofuran (2 ml). The crude adduct was dissolved intetrahydrofuran (6 ml) and treated with tetrabutylammonium fluoridehydrate (0.20 g). After 16 hours, the solution was diluted with water(30 ml) and extracted with ether (2×30 ml). The organic extracts weredried over anhydrous magnesium sulfate, filtered and evaporated underreduced pressure. The residue was purified by column chromatography oversilica, eluting with ether and was then recrystallised from ethylacetate/hexane to give the title compound (0.098 g).

m.p. 130-131° C.

MS (APCI) 469 ((M+H)⁺),

¹H NMR (CDCl₃) δ0.88 (6H, d); 1.90 (2H, quin); 2.10-2.24 (1H, m); 2.84(1H, t); 3.17 (2H, t); 3.42 (3H, s); 3.63 (2H, d); 3.89 (2H, q); 4.78(2H, s); 7.35 (1H, d); 7.44 (1H, t); 7.45-7.56 (2H, m); 7.82 (1H, d);7.84-7.92 (1H, m); 8.01-8.07 (1H, m).

EXAMPLE 7 Methyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-y)thio]butanoate

a) 4,4,4-Trimethoxybutyl para-toluenethiosulphonate

A suspension of para-toluenethiosulphonic acid potassium salt (8.77 g),trimethyl 4-bromoorthobutyrate (8.00 g) and 18-crown-6 (10.24 g) inanhydrous tetrahydrofuran (60 ml) was ultrasonicated for 5 minutes thenstirred at room temperature for 3 days. The mixture was poured intosaturated aqueous sodium bicarbonate solution (200 ml) and extractedwith ether (2×200 ml). The organic extracts were dried over anhydroussodium sulfate, filtered and evaporated under reduced pressure to givethe subtitle compound (10.52 g) as an oil.

¹H NMR (C₆D₆) δ1.57-1.62 (2H, m); 1.64-1.75 (2H, m); 1.86 (3H, s); 2.88(2H, t); 3.06 (9H, s); 6.73 (2H, d); 7.84 (2H, d).

b) Methyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]butanoate

Prepared according to the procedure described in Example 5 fromn-butyllithium (2.5M solution in hexanes, 0.77 ml) and diisopropylamine(0.277 ml) in anhydrous tetrahydrofuran (5 ml),3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(0.20 g) in anhydrous tetrahydrofuran (10 ml) and 4,4,4-trimethoxybutylpara-toluenethiosulphonate (0.799 g) in anhydrous tetrahydrofuran (5ml). The reaction was quenched with hydrochloric acid (0.5M, 20 ml),diluted with ether (20 ml) and stirred for 10 minutes. The phases wereseparated and the aqueous phase extracted with further ether (20 ml).The combined organic extracts were dried over anhydrous magnesiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by column chromatography over silica, eluting with ether:hexane(1:1) to give the title compound (0.365 g) as a solid.

m.p. 111-112° C.

MS (APCI) 511.0 ((M+H)⁺),

¹H NMR (CDCl₃) δ0.87 (6H, d); 1.98 (2H, quin); 2.10-2.20 (1H, m); 2.52(2H, t); 3.10 (2H, t); 3.42 (3H, s); 3.62 (2H, d); 3.67 (3H, s); 4.76(2H, s); 7.35 (1H, d); 7.45 (1H, t); 7.48-7.55 (2H, m); 7.81 (1H, d);7.86-7.92 (1H, m); 7.99-8.04 (1H, m).

EXAMPLE 84-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]butanoicacid

Aqueous sodium hydroxide solution (1M, 4 ml) was added to a solution ofmethyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]butanoate(0.382 g) in methanol (8 ml) and tetrahydrofuran (4 ml). The mixture wasstirred at room temperature for 4 hours, diluted with water (50 ml),acidified with hydrochloric acid (2M) and extracted with an ether/ethylacetate mixture (5:3, 80 ml). The organic extracts were dried overanhydrous magnesium sulfate, filtered and evaporated under reducedpressure. The residual solid was recrystallised from ethylacetate/hexane to give the title compound (0.19 g).

m.p. 172-173° C.

MS (APCI) 497 ((M+H)⁺),

¹H NMR (DMSO-D₆) δ0.80 (6H, d); 1.78 (2H, quin); 1.97-2.15 (1H, m); 2.37(2H, t); 3.04 (2H, t); 3.24 (3H, s); 3.58 (2H, d); 4.76 (2H, s); 7.42(1H, d); 7.49 (1H, t); 7.53-7.59 (2H, m); 7.88 (1H, d); 7.96 (1H, dd);8.06 (1H, d); 12.12 (1H, s, br).

EXAMPLE 9 Methyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)sulfinyl]butanoate

Potassium peroxymonosulfate (0.163 g) was added to a stirred suspensionof methyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]butanoate(0.246 g) in methanol (3 ml), tetrahydrofuran (3 ml) and water (3 ml).After 1 hour, the reaction mixture was poured into saturated aqueoussodium bicarbonate solution (20 ml) and extracted with ethyl acetate(2×20 ml) The organic extracts were dried over anhydrous magnesiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by column chromatography eluting with hexane:ethyl acetate(1:1) followed by trituration with ethyl acetate/hexane to give thetitle compound (0.80 g)

m.p. 160-161° C.

MS (APCI) 527.1 ((M+H)⁺),

¹H NMR (DMSO-D₆) δ0.77 (3H, d); 0.79 (3H, d); 1.95-2.09 (2H, m);2.10-2.25 (1H, m); 2.56 (2H, t); 3.19 (3H, s); 3.20-3.33 (2H, m); 3.46(1H, dd); 3.58-3.64 (4H, m); 4.74 (1H, d); 5.58 (1H, d); 7.50-7.59 (4H,m); 7.90 (1H, d); 7.97 (1H, d); 8.21 (1H, d).

EXAMPLE 10 Methyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)sulfonyl]butanoate

3-Chloroperoxybenzoic acid (57-86%, 0.366 g) was added to a solution ofmethyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]butanoate(0.36 g) in dichloromethane (20 ml). After 1 hour, the solution wasdiluted with ethyl acetate (40 ml) and then washed with saturatedaqueous sodium metabisulfite solution (20 ml) followed by saturatedaqueous sodium bicarbonate solution (20 ml). The organic layer was driedover anhydrous magnesium sulfate, filtered and evaporated under reducedpressure. The residue was crystallised from ethyl acetate/hexane to givethe title compound (0.182 g).

m.p. 122-124° C.

MS (APCI) 543.0 ((M+H)⁺),

¹H NMR (CDCl₃) δ0.81 (6H, d); 1.98-2.15 (1H, m); 2.30 (2H, quin); 2.61(2H, t); 3.40 (3H, s); 3.54 (2H, d); 3.71 (3H, s); 3.94 (2H, t); 5.10(2H, s); 7.43-7.58 (4H, m); 7.86-7.94 (3H, m).

EXAMPLE 114-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)sulfonyl]butanoicacid

Sodium hydroxide solution (1M, 1 ml) was added to a stirred suspensionof methyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)sulfonyl]butanoate(0.10 g) in methanol (3 ml) and tetrahydofuran (3 ml). After 4 hours,the reaction mixture was diluted with water (20 ml), acidified withhydrochloric acid (2M) and extracted with ethyl acetate (2×30 ml). Theorganic extracts were evaporated under reduced pressure. The residue waspartitioned between ether (30 ml) and aqueous sodium hydroxide solution(0.1M, 30 ml). The aqueous phase was acidified with hydrochloric acid(2M) and extracted with ethyl acetate (2×30 ml). The organic extractswere dried over anhydrous magnesium sulfate, filtered and evaporatedunder reduced pressure. The residue was triturated with ethylacetate/hexane to is give the title compound (0.028 g).

m.p. 174-1 75° C.

MS (APCI) 529.0 ((M+H)⁺),

¹H NMR (DMSO-D₆) δ0.77 (6H, d); 1.92-2.05 (3H, m); 2.43 (2H, t); 3.24(3H, s); 3.55 (2H, d) 3.85 (2H, t); 5.10 (2H, s); 7.46-7.61 (4H, m);7.95 (1H, d); 7.97-8.04 (2H, m); 12.22 (1H, s, br).

EXAMPLE 126-Benzyl-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

a) Ethyl 2-amino-5-(phenylmethyl)thiophene-3-carboxylate

Triethylamine (10.40 ml) was added to a solution of 3-phenylpropanal(10.0 g), ethyl cyanoacetate (7.95 ml) and sulfur (2.40 g) indimethylformamide (30 ml). The mixture was heated at 50° C. undernitrogen for 3 hours, then diluted with water (350 ml) and extractedwith diethyl ether four times. The organic extracts were dried overanhydrous magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography eluting withdiethyl ether:isohexane (1:3) to give the subtitle compound (14.2 g).

MS (APCI) 262 ((M+H)⁺)

¹H NMR (CDCl₃) δ1.33 (3H, t); 3.91 (2H, s); 4.25 (2H, q); 5.78 (2H, bs);6.70 (1H, s); 7.20-7.33 (5H, m)

b) Ethyl 2-(2-methylpropylamino)-5-(phenylmethyl)thiophene-3-carboxylate

Sodium borohydride (3.0 g) was added in 6 portions over 3 hours to astirred solution of ethyl2-amino-5-(phenylmethyl)thiophene-3-carboxylate in 2-methylpropanoicacid under nitrogen. The mixture was stirred at room temperature for 20hours and was then diluted with water, neutralized with sodiumbicarbonate and extracted with ethyl acetate four times. The organicextracts were dried over anhydrous magnesium sulfate, filtered andevaporated under reduced pressure. The residue was purified by columnchromatography, eluting with diethyl ether:isohexane (1:19) to give thesubtitle compound (2.80 g).

MS (APCI) 318 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.96 (6H, d); 1.32 (3H, t); 1.93 (1H, m); 2.97 (2H, dd);3.92 (2H, s); 4.23 (2H, q); 6.75 (1H, s); 7.20-7.34 (5H, m); 7.46 (1H,m)

c)N′-Acetyl-N-(2-methylpropyl)-N-[3-ethoxycarbonyl-5-(phenylmethyl)-2-thienyl]urea

Acetyl chloride (0.69 ml) was added to a stirred suspension of silvercyanate (1.51 g) in anhydrous toluene (30 ml) under nitrogen. After 1hour, ethyl2-(2-methylpropylamino)-5-(phenylmethyl)thiophene-3-carboxylate (2.55 g)was added and stirring was continued for 20 hours. The mixture wasfiltered and the solid residue was washed with diethyl ether. Thecombined liquors were evaporated under reduced pressure and the residuewas purified by column chromatography eluting with diethylether:isohexane (1:1) to give the subtitle compound (3.08 g).

MS (APCI) 403 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.88 (6H, d); 1.31 (3H, t); 1.92 (1H, m); 2.46 (3H, s);2.80-3.90 (2×1H, 2 vbs); 4.08 (2H, s); 4.27 (2H, q); 7.08 (1H, s);7.25-7.39 (5H, m); 7.46 (1H, m)

d)3-Methyl-1-(2-methylpropyl)-6-(phenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

Sodium ethoxide (1.96 g) was added to a solution ofN′-acetyl-N-(2-methylpropyl)-N-[3-ethoxycarbonyl-5-(phenylmethyl)-2-thienyl]urea(2.90 g) in ethanol (40 ml) under nitrogen. The mixture was stirred for20 hours then iodomethane (1.80 ml) was added. The mixture was heated toreflux for 3 hours and then allowed to cool to room temperature andevaporated under reduced pressure. The residue was diluted with waterand extracted with ethyl acetate twice. The organic extracts were driedover anhydrous magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography eluting withdiethyl ether:isohexane (1:1) to give an oil which was recrystallisedfrom diethyl ether/isohexane to give the title compound (1.70 g).

m.p. 72-3° C.

MS (APCI) 329 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.95 (6H, d); 2.28 (1H, m); 3.41 (3H, s); 3.72 (2H, d);4.07 (2H, s); 7.05 (1H, s); 7.23-7.37 (5H, m)

EXAMPLE 133-Methyl-1-(1-methylethyl)-6-(phenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

a) 2-(1-methylethylamino)-5-(phenylmethyl)thiophene-3-carboxylic acid,ethyl ester

To a solution of 2-amino-5-(phenylmethyl)thiophene-3-carboxylic acid,ethyl ester (2.61 g) and 4-methylbenzenesulfonic acid (30 mg) in drytoluene (50 ml) was added 2,2-dimethoxypropane. The solution was heatedto reflux for 5 hours and then allowed to cool to ambient temperature. Asolution of sodium borohydride (800 mg) in ethanol (100 ml) was added tothe solution and the mixture was stirred at room temperature undernitrogen for 24 hours. The mixture was diluted with water and thenextracted thrice with ethyl acetate. The combined organic extracts werewashed with brine and then dried over anhydrous magnesium sulfate,filtered and evaporated under reduced pressure to give an oil. Theresidue was purified by column chromatography over silica, eluting withdiethyl ether: isohexane (1:19) to give the subtitle compound (550 mg).

MS (APCI) 304 ((M+H)⁺)

¹H NMR (CDCl₃) δ1.25 (6H, d); 1.31 (3H, t); 3.41 (1H, m); 3.93 (2H, s);4.22 (2H, q); 6.74 (1H, s); 7.20-7.33 (5H, m)

b)N′-acetyl-N-(1-methylethyl)-N-[3-ethoxycarbonyl-5-(phenylmethyl)-2-thienyl]urea

Prepared from2-(1-methylethylamino)-5-(phenylmethyl)thiophene-3-carboxylic acid,ethyl ester (550 mg), silver cyanate (340 mg) and acetyl chloride (0.155ml) following the method of Example 12, step c) to give the subtitlecompound.

MS (APCI) 389 ((M+H)⁺)

c)3-methyl-1-(1-methylethyl)-6-(phenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

Prepared fromN′-acetyl-N-(1-methylethyl)-N-[3-ethoxycarbonyl-5-(phenylmethyl)-2-thienyl]urea(700 mg), sodium ethoxide (400 mg) and iodomethane (0.45 ml) followingthe method of Example 12, step d) to give the title compound.

m.p. 91-3° C.

MS (APCI) 315 ((M+H)⁺)

¹H NMR (CDCl₃) δ1.55 (6H, d); 3.38 (3H, s); 4.07 (2H, s); 4.60 (1H, bs);7.07 (1H, s); 7.23-7.37 (5H, m)

EXAMPLE 146-[(1-Hydroxy-1-phenyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

A solution of3-methyl-1-(2-methylpropyl)-6-(phenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(Example 12, 0.150 g) and N-bromosuccinimide (0.090 g) in anhydrouschloroform (5 ml) was heated to reflux under nitrogen for 2 hours. Themixture was evaporated under reduced pressure and the residue waspurified by column chromatography eluting with diethyl ether:isohexane(1:1) to give the title compound (0.085 g).

m.p. 140-2° C.

MS (APCI) 345 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.97 (6H, d); 2.31 (1H, m); 2.57 (1H, d); 3.39 (3H, s);3.77 (2H, ddd); 5.97 (1H, d); 7.03 (1H, s); 7.33-7.46 (5H, m)

EXAMPLE 15 (±)5-[(2-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

a) (±) and meso Bis 2-hydroxypropyldisulride

1-Mercaptopropan-2-ol (2 ml) was dissolved in dichloromethane (10 ml).Sodium bicarbonate (2.67 g) and water (10 ml) were added. The suspensionwas stirred vigorously and cooled in an ice bath. A solution of bromine(0.59 ml) in dichloromethane (5 ml) was added dropwise to thesuspension. The mixture was stirred for 10 minutes after addition wascomplete, then the phases were separated. The aqueous phase wasextracted with dichloromethane, the dichloromethane phases werecombined, then dried, filtered and evaporated to give the subtitlecompound (2.56 g).

¹H NMR (CDCl₃) δ1.29 (6H, d), 2.33 (2H, br), 2.67-2.75 (2H, m),2.83-2.92 (2H, m), 4.05-4.12 (2H, m).

b) (±) and meso Bis2-[(1,1-dimethylethyl)(dimethyl)silyloxy]propyldisulfide

(±) And meso bis 2-hydroxypropyldisulfide (2.56 g) was dissolved indimethyformamide (20 ml). Imidazole (1.60 g) anddimethyl(1,1-dimethylethyl)silyl chloride (3.46 g) were added and theresulting solution was stirred overnight. The reaction mixture waspoured into water (100 ml) and extracted thrice with ether. The etherextracts were combined, washed with brine, dried, filtered andevaporated. Chromatography, eluting with isohexane:ether (99:1), gavethe subtitle compound (3.90 g).

¹H NMR (CDCl₃) δ0.08 (6H, s), 0.09 (6H, s), 0.89 (18H, s), 1.24 (6H, d),2.63-2.70 (2H, m), 2.79-2.87 (2H, m), 4.00-4.07 (2H, m).

c) (±)5-[(2-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylnethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(Example 2) (220 mg) was dissolved in tetrahydrofuran (1 ml) and cooledto −78°. LDA (1M solution in tetrahydrofuran/hexane) was added dropwiseuntil a red colour persisted. The solution was stirred for 1 h then asolution of (±) and meso bis 2-[dimethyl(1,1-dimethylethyl)silyloxy]propyldisulfide (298 mg) in tetrahydrofuran (3 ml) was addedand the solution was allowed to warm to 0° C. After 65 minutes sodiumbicarbonate (aqueous) was added and the mixture was extracted thricewith ethyl acetate. The ethyl acetate phases were combined, washed withbrine, dried, filtered and evaporated. Chromatography eluting withisohexane:ethyl acetate (9:1 to 4:1) gave the silyl ether of the titlecompound (MS (+ve APCI) 583 (M+H)⁺). The silyl ether was dissolved inacetonitrile (3 ml), hydrofluoric acid (40% aqueous, 0.6 ml) was addedand the solution was stirred for 40 minutes. Sodium bicarbonate(aqueous) was added and the reaction mixture was extracted thrice withethyl acetate. The ethyl acetate phases were combined, washed withbrine, dried, filtered and evaporated. Chromatography, eluting withisohexane:ethyl acetate (3:1) changing to ethyl acetate followed by HPLC(isohexane:ethyl acetate 50:50 to 0:100), gave the title compound (28mg).

m.p. 126-128°

MS (+ve APCI) 469 ((M+H)⁺)

¹H NMR (DMSO d-6) δ0.81 (6H, d), 1.17 (3H, d), 1.98-2.11 (1H, m),2.89-2.95 (1H, m), 3.00-3.06 (1H, m), 3.25 (3H, s), 3.59 (2H, d),3.70-3.81 (1H, m), 4.79 (2H, s), 4.84 (1H, d), 7.41 (1H. d), 7.49 (1H,t), 7.52-7.58 (2H, m), 7.88 (1H, d), 7.93-7.98 (1H, m) and 8.08-8.11(1H,m).

EXAMPLE 161,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide

a)1,2,3,4-Tetrahydro-3-methyl-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylicacid

n-Butyllithium (2.0M solution in hexanes, 1.90 ml) was added dropwise toa solution of diisopropylamine (0.069 ml) in anhydrous tetrahydrofuran(30 ml) at 0° C., under nitrogen. The solution was stirred for 5 minutesthen cooled to −78° C. and a solution of3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(1.50 g) in anhydrous tetrahydrofuran (15 ml) was added dropwise. After15 minutes, the flask was transferred to a sealed bomb containing carbondioxide pellets (2 g) and heated to 50° C. for 18 hours. The reactionmixture was cooled to room temperature then added to aqueous sodiumhydroxide solution (0.25M, 75 ml) and washed with ether (2×75 ml). Theaqueous layer was acidified with concentrated hydrochloric acid andextracted with ether (2×75 ml). The organic extracts were dried overanhydrous magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography over silica,eluting with isohexane:ethyl acetate (3:1) containing 1% acetic acid, togive the subtitle compound (0.337 g) as a solid.

MS (+ve APCI) 423 ((M+H)⁺)MS.

¹H NMR (DMSO d₆) δ0.79 (6H, d), 1.96-2.10 (1H, m), 3.25 (3H, s), 3.58(2H, d), 4.75 (2H, d), 7.49-7.55 (4H, m), 7.88-7.91 (1H, m), 7.95-7.98(1H, m), 8.09-8.12 (1H, m).

b)1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide

To a solution of1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylicacid (50 mg) and 2-aminoethanol (14 μl) in dichloromethane (2 ml) wasadded 1-hydroxybenzotriazole hydrate (48 mg) followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45 mg). Thereaction mixture was stirred at room temperature for 18 hours thenhydrochloric acid (1M, 20 ml) was added and the mixture was extractedwith ether (30 ml). The organic extracts were washed with water, thenwith 1M sodium hydroxide solution, dried over anhydrous magnesiumsulfate, filtered and evaporated under reduced pressure. The residue wasrecrystallised from ethyl acetate:isohexane to give the title compound(28 mg).

m.p. 193-194° C.

MS (+ve APCI) 466 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.84 (6H, d), 2.05-2.20 (1H, m), 3.41 (3H, s), 3.57-3.70(5H, m), 3.91 (2H, q), 4.92 (2H, s), 7.42-7.52 (4H, m), 7.82-7.90 (2H,m), 8.04-8.08 (1H, m), 8.38 (1H, t, br).

The following compounds were prepared according to the method of Example16 using1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylicacid (Example 15a) and the appropriate amine.

MS m.p./ (+ve APCI) Example Compound ° C. ((M + H)⁺) ¹H NMR δ 17(3R)-1-{[1,2,3,4-Tetrahydro-3- 198- 492 (DMSO d₆) 0.79-0.86 (6H, m),1.55- methyl-1-(2-methylpropyl)-6-(1- 199 2.15 (3H, m), 2.70-2.97 (1H,m), naphthalenylmethyl)-2,4- 3.19 (3H, s), 3.19-3.30 (1H, m),dioxothieno[2,3-d]pyrimidin-5-yl]- 3.40-3.68 (4H, m), 3.97-4.58 (3H,carbonyl}pyrrolidin-3-ol m), 4.83-5.07 (1H, m), 7.43-7.58 (4H, m),7.83-7.98 (2H, m), 8.10- 8.22 (1H, m).

18 1-{[1,2,3,4-Tetrahydro-3-methyl-1- 210- 506 (CDCl₃) 0.89-0.92 (6H,m), 1.08- (2-methylpropyl)-6-(1-naphthalenyl- 211 1.19 + 1.39-1.56 +1.70-1.90 + methyl)-2,4-dioxothieno[2,3-d]- 2.00-2.25 (5H, m), 3.36 (3H,s), pyrimidin-5-yl]-carbonyl}piperidin-4- 2.70-2.80 + 3.06-3.31 +3.38-3.59 + ol 3.66-3.83 + 3.85-3.99 (7H, m), 4.16-4.37 (1H, m),4.40-4.58 (2H, m), 7.38-7.57 (4H, m), 7.79-7.92 (2H, m), 8.02-8.08 (1H,m).

19 (3R)-1-{[1,2,3,4-Tetrahydro-3- 506 (DMSO d₆) 0.81-0.88 (6H, m),methyl-1-(2-methylpropyl)-6-(1- 1.20-1.59 + 1.67-1.97 (4H, m),naphthalenylmethyl)-2,4- 2.00-2.15 (1H, m), 2.57-2.95 +dioxothieno[2,3-d]pyrimidin-5-yl]- 2.99-3.19 (2H), 3.11-3.74 (7H, m),carbonyl}piperidin-3-ol 3.90-4.08 + 4.18-4.58 (3H), 4.72- 4.96 (1H, m),7.49-7.55 (4H, m), 7.85-7.91 (1H, m), 7.93-7.98 (1H, m), 8.12-8.19 (1H,m).

20 1,2,3,4-Tetrahydro-N-(2-hydroxy- 129- 480 (DMSO d₆) 0.78-0.81 (6H,m), 1.98- ethyl)-3,N-dimethyl-1-(2-methyl- 130 2.03 (1H, m), 2.78 (s) +3.05 (s) propyl)-6-(1-naphthalenylmethyl)- (3H), 3.21 (3H, s), 3.04-3.73(6H, 2,4-dioxothieno[2,3-d]pyrimidine- m), 4.34-4.56 (2H, m), 4.66-4.775-carboxamide (1H, m), 7.45-7.57 (4H, m), 7.88 (1H, d), 7.92-7.99 (1H,m), 8.13- 8.26 (1H, m).

EXAMPLE 212-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carboxamido}aceticacid

Oxalyl chloride (0.092 ml) was added to a solution of1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylicacid (Example 15a, 222 mg) and dimethylformamide (0.01 ml) in anhydrousdichloromethane (5 ml) at room temperature. After 2 hours, the solutionwas evaporated under reduced pressure to give1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carbonylchloride as an oil. A solution of this oil (58 mg) in anhydrousdichloromethane (2 ml) was added to a stirred mixture of glycine methylester hydrochloride (29 mg) and triethylamine (0.037 ml) in anhydrousdichloromethane (1 ml) at room temperature. After I hour, ethyl acetate(25 ml) and 2M hydrochloric acid were added. The organic layer waswashed with water then with saturated sodium hydrogen carbonatesolution, dried over anhydrous magnesium sulfate, filtered andevaporated under reduced pressure The residue was dissolved in a mixtureof tetrahydrofuran (4 ml), methanol (2 ml) and 1M sodium hydroxidesolution (1 ml). After 2 hours, water (20 ml) was added and the solutionwas extracted with ether (20 ml). The aqueous layer was acidified withhydrochloric acid and then extracted with ethyl acetate (3×20 ml). Theorganic extracts were dried over anhydrous magnesium sulfate, filteredand evaporated under reduced pressure. The residue was recrystallisedfrom ethyl acetate:isohexane to give the title compound (42 mg).

m.p. 218-219° C.

MS (+ve APCI) 480 ((M+H)⁺)

¹H NMR (CDCl₃/DMSO d₆) δ0.83 (6H, d), 2.06-2.15 (1H, m), 3.41 (3H, s),3.59 (2H, d), 4.23 (2H, d), 5.00 (2H, s), 7.43-7.54 (4H, m), 7.80-7.90(2H, m), 8.01-8.06 (1H, m) 9.73 (1H, t).

The following Examples were prepared according to the method of Example21 using1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carbonylchloride (prepared in Example 19) and the appropriate amine (excludingthe hydrolysis step for Examples 23 and 24).

MS m.p./ (+ve APCI) Example Compound ° C. ((M + H)⁺) ¹H NMR (DMSO d₆) δ22 3-{[1,2,3,4-Tetrahydro-3-methyl-1- 191- 494 0.79 (6H, d), 1.98-2.07(1H, m), (2-methylpropyl)-6-(1-naphthalenyl- 192 2.57 (2H, t), 3.22 (3H,s), 3.49 (2H, methyl)-2,4-dioxothieno[2,3-d]- q), 3.57 (2H, d), 4.56(2H, s), 7.43- pyrimidin-5-yl]-carboxamido}- 7.57 (4H, m), 7.88 (1H,dd), 7.92- propanoic acid 7.98 (1H, m), 8.16-8.20 (1H, m), 8.59 (1H, t).

23 2-{[1,2,3,4-Tetrahydro-3-methyl-1- 235- 479 0.80 (6H, d), 1.98-2.10(1H, m), (2-methylpropyl)-6-(1-naphthalenyl- 236 3.24 (3H, s), 3.60 (2H,d), 3.81 (2H, methyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]- d), 4.61(2H, s), 7.30 (1H, s), 7.46- carboxamido}acetamide 7.56 (4H, m), 7.79(1H, s), 7.88 (1H, d), 7.92-7.96 (1H, m), 8.19-8.23 (1H, m), 8.95 (1H,t).

24 1-{[1,2,3,4-Tetrahydro-3-methyl-1- 171- 476 0.84 (6H, d), 1.44-1.60(1H, m), (2-methylpropyl)-6-(1-naphthalenyl- 172 1.61-1.82 (3H, m),2.02-2.17 (1H, methyl)-2,4-dioxothieno[2,3-d]- m), 2.64-2.75 (1H, m),2.98-3.08 pyrimidin-5-yl]-carbonyl}- (1H, m), 3.19 (3H, s), 3.33-3.48(2H, pyrrolidine m), 3.56-3.70 (2H, m), 4.49 (2H, Abq), 7.49-7.56 (4H,m), 7.84-7.92 (1H, m), 7.95-7.98 (1H, m), 8.13- 8.17 (1H, m).

EXAMPLE 251,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-sulfonamide

a) Lithium1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-sulfinate

A solution of lithium diisopropylamide (3.52 mmol) in anhydroustetrahydrofuran (10 ml) was added dropwise to a solution of of3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(1.00 g) in anhydrous tetrahydrofuran (20 ml) at −78° C. under nitrogen.After 15 minutes, sulfur dioxide was bubbled through the reactionmixture which was warmed to room temperature over 30 minutes. Nitrogenwas then bubbled through the solution for 10 minutes. The precipitatedsolid was filtered, washed with ether and dried in vacuo at 50° C. togive the subtitle compound (1.20 g).

MS (+ve APCI) 425 ((M+H−HOLi)⁺)

¹H NMR (DMSO d₆) δ0.75 (6H, d), 1.85-2.06 (1H, m), 3.21 (3H, s), 3.50(2H, d), 5.22 (1H, s), 7.43-7.51 (3H, m), 7.55 (1H, d), 7.83 (1H, d),7.90 (1H, dd), 8.54 (1H, dd).

b)1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-sulfonamide

N-Chlorosuccinimde (52 mg) was added to a rapidly stirred suspension oflithium1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-sulfinate(200 mg) in dichloromethane (8 ml) and 0.22M hydrochloric acid (9 ml).After I hour, further N-chlorosuccinimide (26 mg) was added. After Ihour, water (30 ml) and dichloromethane (30 ml) were added and thephases were separated. The aqueous phase was extracted withdichloromethane (2×10 ml). The combined organic extracts were treatedwith ethanolamine (0.071 ml). After 30 minutes, the solution was washedwith saturated sodium hydrogen carbonate solution, dried over anhydrousmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography over silica, eluting withether to give the title compound (120 mg) as a foam.

MS (+ve APCI) 502 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.82 (6H, d), 2.01-2.16 (1H, m), 3.32 (2H, q), 3.41 (3H,s), 3.79-3.85 (2H, m), 5.05 (2H, s), 7.41-7.56 (4H, m), 7.59 (1H, t),7.83-7.98 (3H, m).

EXAMPLE 265-[(3-Methoxyphenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione

A solution of lithium diisopropylamide (3.09mmol) in anhydroustetrahydrofuran (10 ml) was added dropwise to a solution of3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(1.00 g) in anhydrous tetrahydrofuran (25 ml) at −78° C. under nitrogen.After 15 minutes, bis-(3-methoxyphenyl)disulfide (J. Amer. Chem. Soc.;75; 1953; 5736) (0.88 g) was added and the mixture was allowed to warmto room temperature. The mixture was added to saturated sodium hydrogencarbonate solution (100 ml) and extracted with ether (2×100 ml). Theorganic extracts were dried over anhydrous magnesium sulfate, filteredand evaporated under reduced pressure. The residue was purified bycolumn chromatography over silica, eluting with isohexane:ether (1:1) togive the title compound (1.00 g) as an oil.

MS (+ve APCI) 517 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.88 (6H, d), 2.13-2.22 (1H, m), 3.34 (3H, s), 3.62 (2H,d), 3.76 (3H, s), 4.71 (2H, s), 6.71 (1H, dt), 6.79 (1H, t), 6.81 (1H,d), 7.20 (1H, t), 7.37-7.52 (4H, m), 7.81 (1H, d), 7.86 (1H, d), 7.89(1H, d).

EXAMPLE 275-[(3-Hydroxyphenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione

Boron tribromide (1M solution in dichloromethane, 5.63 ml) was added toa stirred solution of5-[(3-methoxyphenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione(Example 26, 0.97 g) in anhydrous dichloromethane (50 ml) at 0° C. undernitrogen. After I hour, saturated sodium hydrogen carbonate solution(100 ml) was added and the mixture was extracted with ethyl acetate(2×100 ml). The organic extracts were dried over anhydrous magnesiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by column chromatography over silica, eluting with ethylacetate:isohexane (3:2) and then recrystallised from ethylacetate:isohexane to give the title compound (0.468 g).

m.p. 200-201° C.

MS (+ve APCI) 503 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.82 (6H, d), 2.00-2.11 (1H, m), 3.17 (3H, s), 3.61(2H, d), 4.73 (2H, s), 6.56 (1H, t), 6.58 (1H, dt), 6.64 (1H, dt), 7.11(1H, t), 7.35 (1H, td), 7.45-7.52 (3H, m), 7.86-7.90 (2H, m), 7.94 (1H,d), 9.49 (1H, s).

EXAMPLE 285-[(3-Hydroxyphenyl)sulfinyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione

3-Chloroperoxybenzoic acid (0.12 g) was added to a solution of5-[(3-hydroxyphenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione(Example 27, 0.20 g) in dichloromethane (5 ml). After 2 hours, ethylacetate (50 ml) was added and the solution was washed with saturatedsodium bisulfite solution (25 ml), then with saturated sodium hydrogencarbonate solution (25 ml), then with brine (25 ml). The organic layerwas dried over anhydrous magnesium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by preparativenormal-phase HPLC with dichloromethane:ethanol gradient elution thenrecrystallised from ethyl acetate:isohexane to give the title compound(0.05 g).

m.p. 242-243° C.

MS (+ve APCI) 519 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.74 (3H, d), 0.75 (3H, d), 1.88-2.02 (1H, m), 3.25(3H, s), 3.49 (2H, d), 4.58 (1H, d), 5.37 (1H, d), 6.95 (1H, dt),7.24-7.36 (3H, m), 7.42 (1H, t), 7.45-7.55 (3H, m), 7.67 (1H, d), 7.89(1H, d), 7.94 (1H, d).

EXAMPLE 295-[(3-Hydroxyphenyl)sulfonyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenerimidine-2,4-(1H,3H)-dione

3-Chloroperoxybenzoic acid (50 mg) was added to a solution of5-[(3-hydroxyphenyl)sulfinyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione(Example 28, 80 mg) in dichloromethane (2 ml). After 2 hours, ethylacetate (25 ml) was added and the solution was washed with saturatedsodium bisulfite solution (10 ml), then with saturated sodium hydrogencarbonate solution (10 ml), then with brine (10 ml). The organic layerwas dried over anhydrous magnesium sulfate, filtered and evaporatedunder reduced pressure. The residue was recrystallised from ethylacetate:isohexane to give the title compound (24 mg).

m.p. 209-210° C.

MS (+ve APCI) 535 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.76 (6H, d), 1.89-2.01 (1H, m), 3.11 (3H, s), 3.52(2H, d), 5.25 (2H, s), 7.05 (1H, dt), 7.38-7.68 (7H, m), 7.94 (1H, dd),7.99-8.07 (2H, m).

EXAMPLE 303-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(3-nitrophenyl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione

A solution of lithium diisopropylamide (3.63 mmol) in anhydroustetrahydrofuran (5.5 ml) was added dropwise to a solution of3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(1.0 g) in anhydrous tetrahydrofuran (20 ml) at −78° C. under nitrogen.After 15 minutes, bis(3-nitrophenyl) disulfide (0.90 g) was added andthe mixture was warmed to room temperature over 1 hour. Saturated sodiumhydrogen carbonate solution (100 ml) was added and the mixture wasextracted with ether (2×100 ml). The organic extracts were dried overanhydrous magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography over silica,eluting with ethyl acetate:isohexane (1:1) to give partially purifiedmaterial (1.40 g). A portion of this material (0.20 g) was furtherpurified by preparative normal-phase HPLC with dichloromethane:ethanolgradient elution and then recrystallised from ethyl acetate:isohexane togive the title compound (22 mg).

m.p. 144-145° C.

MS (+ve APCI) 532 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.91 (6H, d), 2.12-2.28 (1H, m), 3.31 (3H, s), 3.66 (2H,d), 4.75 (2H, s), 7.36-7.53 (5H, m), 7.56 (1H, dt), 7.82 (1H, d), 7.88(1H, d), 7.92 (1H, d), 7.95 (1H, t), 8.00 (1H, dt).

EXAMPLE 315-[(3-Aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione

A suspension of the partially purified3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(3-nitrophenyl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Example 30, 1.20 g), iron powder (0.59 g) and ammoniumchloride (0.56 g) in ethanol (5 ml) and water (5 ml) was heated atreflux for 2 hours, then cooled to room temperature. 2M Sodium hydroxidesolution (50 ml) was added and the mixture was stirred for 30 minutes.The resulting solution was decanted from insoluble solid. The solid andsolution were in turn extracted with ethyl acetate (3×50 ml). Thecombined organic extracts were dried over anhydrous magnesium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby column chromatography over silica, eluting with ether:isohexane (2:1)followed by recrystallisation from ethyl acetate:isohexane to give thetitle compound (0.41 g).

m.p. 149-150° C.

MS (+ve APCI) 502 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.88 (6H, d), 2.10-2.23 (1H, m), 3.35 (3H, s), 3.62 (2H,d), 3.63 (2H, s), 4.71 (2H, s), 6.48 (1H, dt), 6.59 (1H, t), 6.64 (1H,dt), 7.06 (1H, t), 7.37-7.50 (4H, m), 7.80-7.92 (3H, m).

EXAMPLE 325-{[3-{(Bis-methanesulfonyl)amino}phenyl]thio}-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethy)theino[2,3d]pyrimidine-2,4(1H,3H)-dione

Methanesulfonyl chloride (0.028 ml) was added to a solution of5-[(3-aminophenyl)thiol-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (60 mg) and triethylamine (0.067 ml) in anhydrousdichloromethane (2 ml) at room temperature. After 1 hour, saturatedsodium hydrogen carbonate solution (10 ml) was added and the mixture wasextracted with ether (2×10 ml). The organic extracts were dried overanhydrous magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by preparative normal-phase HPLC withisohexane:ethyl acetate gradient elution then recrystallised from ethylacetate:isohexane to give the title compound (28 mg).

m.p. 216-217° C.

MS (+ve APCI) 658 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.88 (6H, d), 2.10-2.24 (1H, m), 3.29 (3H, s), 3.34 (6H,s), 3.63 (2H, d), 4.72 (2H, s), 7.15-7.18 (2H, m), 7.34-7.51 (6H, m),7.82 (1H, d), 7.87 (1H, d), 7.95 (1H, d).

EXAMPLE 335-[(3-Methoxycarbonylaminophenyl)thiol-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione

Methyl chloroformate (0.028 ml) was added to a solution of5-[(3-aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimiidine-2,4-(1H, 3H)-dione (60 mg) and triethylamine(0.067 ml) in anhydrous dichloromethane (2 ml) at room temperature.Further triethylamine (0.067 ml) and methyl chloroformate (0.028 ml)were added after 4 hours and 24 hours. Saturated sodium hydrogencarbonate solution (10 ml) was added and the mixture was extracted withether (2×10 ml). The organic extracts were dried over anhydrousmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by preparative normal-phase HPLC withdichloromethane:ethanol gradient elution and then recrystallised fromethyl acetate isohexane to give the title compound (15 mg).

m.p. 167-168° C.

MS (+ve APCI) 560 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.89 (6H, d), 2.11-2.24 (1H, m), 3.34 (3H, s), 3.63 (2H,d), 3.74 (3H, s), 4.73 (2H, s), 6.52 (1H, s, br), 6.93 (1H, d),7.17-7.35 (3H, m), 7.35-7.50 (4H, m), 7.80-7.91 (3H, m).

EXAMPLE 345-[(3-Acetamidophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione

Acetic anhydride (0.034 ml) was added to a solution of5-[(3-aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione (60 mg) and triethylamine(0.067 ml) in anhydrous dichloromethane (2 ml) at room temperature.After 1 hour, work-up and purification as in Example 32 gave the titlecompound (15 mg).

m.p. 173-174° C.

MS (+ve APCI) 544 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.88 (6H, d), 2.08-2.24 (1H, m), 2.14 (3H, s), 3.34 (3H,s), 3.63 (2H, d), 4.73 (2H, s), 6.97 (1H, d), 7.08 (1H, s, br), 7.22(1H, t), 7.35-7.50 (6H, m), 7.81 (1H, d), 7.86 (1H, d), 7.91 (1H, d).

EXAMPLE 353-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(4-nitrophenyl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione

A solution of lithium diisopropylamide (2.6 mmol) in anhydroustetrahydrofuran (7.5 ml) was added dropwise to a solution of3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(1.00 g) in anhydrous tetrahydrofuran (20 ml) at −78° C. under nitrogen.After 15 minutes, bis(4-nitrophenyl) disulfide (0.90 g) was added andthe mixture was warmed to room temperature for 16 hours. Saturatedsodium to hydrogen carbonate solution (100 ml) was added and the mixturewas extracted with ether (2×100 ml). The organic extracts were driedover anhydrous magnesium sulfate, filtered through a silica pad andevaporated under reduced pressure to give the crude product (1.4 g). Aportion of this material (0.14 g) was purified by preparativenormal-phase HPLC with dichloromethane:ethanol gradient elution and thenrecrystallised from ethyl acetate isohexane to give the title compound(28 mg).

m.p. 184-185° C.

MS (+ve APCI) 532 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.91 (6H, d), 2.15-2.28 (1H, m), 3.32 (3H, s), 3.66 (2H,d), 4.73 (2H, s), 7.25 (2H, d), 7.33-7.51 (4H, m), 7.82-8.11 (3H, m),8.12 (2H, d).

EXAMPLE 365-[(4-Aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione

A suspension of the crude3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(4-nitrophenyl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Example 35, 1.26 g), iron powder (0.59 g) and ammoniumchloride (0.56 g) in ethanol (5 ml) and water (5 ml) was heated atreflux for 4 hours, then cooled to room temperature. Sodium hydroxidesolution (10%, 50 ml) was added and the mixture was stirred for 1 hour.The resulting solution was decanted from insoluble solid. The solid andsolution were in turn extracted with dichloromethane (3×50 ml) thenethyl acetate (3×50 ml). The combined organic extracts were dried overanhydrous magnesium sulfate, filtered and evaporated under reducedpressure. The residue was partially purified by column chromatographyover silica, eluting with ethyl acetate:isohexane (1:1). Some purematerial was recrystallised from isohexane: ethyl acetate to give thetitle compound (0.065 g). The remaining material was purified bypreparative normal-phase HPLC with dichloromethane:ethanol gradientelution to give the title compound (0.163 g).

m.p. 177-178° C.

MS (+ve APCI) 502((M+H)⁺)

¹H NMR (CDCl₃) δ0.86 (6H, d), 2.07-2.20 (1H, m), 3.37 (3H, s), 3.59 (2H,d), 3.68 (2H, s, br), 4.74 (2H, s), 6.61 (2H, d), 7.28 (2H, d),7.34-7.51 (4H, m), 7.81 (1H, d), 7.87 (1H, d), 7.90 (1H, d).

EXAMPLE 373-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(5-nitropyridin-2-yl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione

A solution of lithium diisopropylamide (6.2 mmol) in anhydroustetrahydrofuran (20 ml) was added dropwise to a solution of3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(2.00 g) in anhydrous tetrahydrofuran (40 ml) at −78° C. under nitrogen.After 20 minutes, 2,2′-dithiobis(5-nitropyridine) (1.97 g) was added andthe mixture was warmed to room temperature for 1 hour. Saturated sodiumhydrogen carbonate solution (200 ml) was added and the mixture wasextracted with ethyl acetate (200 ml). A solid suspended in the organicextracts was collected by filtration, washed with ethyl acetate anddried in vacuo at 40° C. to give the title compound (2.14 g).

m.p. 200-201° C.

MS (+ve APCI) 533 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.91 (6H, d), 2.15-2.29 (1H, m), 3.30 (3H, s), 3.66(2H,d), 4.72 (2H, s), 7.28 (1H, d), 7.35-7.51 (4H, m), 7.81 (1H, d), 7.87(1H, d), 7.93 (1H, d), 8.27 (1H, dd), 9.20 (1H, d).

EXAMPLE 382-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]thio}pyridineN-oxide

A solution of lithium diisopropylamide (1.55 mmol) in anhydroustetrahydrofuran (5 ml) was added dropwise to a solution of3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(0.50 g)) in anhydrous tetrahydrofuran (10 ml) at −78° C. undernitrogen. After 20 minutes, 2,2′-dithiobis(pyridine N-oxide) (0.40 g)was added and the mixture was warmed to room temperature. After 2 hours,saturated sodium hydrogen carbonate solution (100 ml) was added and themixture was extracted with ethyl acetate (3×50 ml). The organic extractswere dried over anhydrous magnesium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by columnchromatography over silica, eluting with ethyl acetate:methanol (19:1)and then recrystallised from ethyl acetate to give the title compound(0.18 g).

m.p. 228-229° C.

MS (+ve APCI) 504 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.86 (6H, d), 2.03-2.16 (1H, m), 3.15 (3H, s), 3.64(2H, d), 4.74 (2H, s), 6.86 (1H, dd), 7.17-7.27 (2H, d), 7.34 (1H, td),7.42-7.53 (3H, m), 7.86 (1H, dd), 7.91 (1H, d), 7.93 (1H, d), 8.36 (1H,dd).

EXAMPLE 395-[(3-Azidopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

a)3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propylmethanesulfonate

5-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylnethyl)thieno-[2,3-d]pyrimidine-2,4(1H,3H)-dione(Example 4) (403 mg) was dissolved in dichloromethane (6 ml).Triethylamine (300 μl) was added followed by methanesulfonyl chloride(150 μl) and the mixture was stirred overnight. Sodium bicarbonate(aqueous) was added and the phases were separated. The aqueous phase wasextracted twice with dichloromethane, the organic phases were combined,washed with brine, dried, filtered and evaporated to give the subtitlecompound (0.57 g).

MS (+ve APCI) 547 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.89 (6H, d), 2.09 (2H, quint), 2.09-2.24 (1H, m), 3.16(2H, t), 3.00 (3H, s), 3.42 (3H, s), 3.64 (2H, d), 4.37 (2H, t), 4.77(2H, s), 7.34 (1H, d), 7.45 (1H, t), 7.51-7.54 (2H, m), 7.82 (1H, d),7.87-7.90 (1H, m), 7.99-8.02 (1H, m).

b)5-[(3-Azidopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propylmethanesulfonate (0.57 g) and sodium azide (501 mg) were suspended indimethylformamide (7 ml). The suspension was sonicated (cleaning bath)for 3 h. Water was added and the suspension was extracted thrice withethyl acetate. The extracts were combined and washed successively withbrine, water and brine, then dried, filtered and evaporated.Chromatography (isohexane:ethyl acetate 4:1 to 3:1) gave a yellow oilwhich was triturated with cyclohexane to give the title compound (118mg).

m.p. 94-96°

MS (+ve APCI) 494 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.81 (6H, d), 1.79 (2H, quin), 1.98-2.10 (1H, m), 3.05(2H, t), 3.25 (3H, s), 3.46 (2H, t), 3.60 (2H, d), 4.78 (2H, s), 7.41(1H, d), 7.50 (1H, t), 7.52-7.59 (2H, m), 7.88 (1H, d), 7.95-7.98 (1H,m), 8.06-8.09 (1H, m).

EXAMPLE 405-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrmidine-2,4(1H,3H)-dione

5[(3-Azidopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(656 mg), 1,3-propanedithiol (100 μl) and triethylamine (400 μl) weredissolved in a mixture of dichloromethane (3 ml) and isopropanol (5 ml).Sodium borohydride (78 mg) was added and the mixture was stirredovernight. The solvents were removed by evaporation then dilutehydrochloric acid was added dropwise until effervescence ceased. Thesolution was made alkaline with aqueous sodium hydroxide and thenextracted with dichloromethane (four times). The extracts were dried,filtered and evaporated. Purification by HPLC (ethanol:dichloromethane5-40:95-60) followed by trituration with ether-cyclohexane gave thetitle compound (280 mg).

MS (+ve APCI) 468 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.88 (6H, d), 1.82 (2H, quint), 2.11-2.22 (1H, m), 2.88(2H, t), 3.12 (2H, t), 3.42 (3H, s), 3.63 (2H, d), 4.78 (2H, s), 7.35(1H, d), 7.45 (1H, t), 7.49-7.52 (2H, m), 7.82 (1H, d), 7.87-7.89 (1H,m) and 8.02-8.04 (1H, m).

5-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(142 mg) was dissolved in dichloromethane-ethanol and 1M HCl in ether (1ml) was added. The solution was evaporated, then the solid wastriturated with ethyl acetate to give the title compound as thehydrochloride salt monohydrate (62 mg).

m.p. 200-205°

elemental: found: C, 57.42%; H, 6.02%; N, 7.87%; S, 11.90%; theory forC₂₅H₃₂ClN₃O₂₂: C, 57.51%; H, 6.18%; N, 8.05%; S, 12.28%;

MS (+ve APCI) 468 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.82 (6H, d), 1.83 (2H, quint), 1.99-2.12 (1H, m),2.94 (2H, t), 3.05 (2H, t), 3.26 (3H, s), 3.61 (2H, d), 4.78 (2H, s),7.40 (1H, d), 7.50 (1H, t), 7.53-7.62 (2H, m), 7.78 (3H, br), 7.89 (1H,d), 7.96-7.99 (1H, m) and 8.06 (1H, d).

EXAMPLE 41N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothien2,3-d]primidin-5-yl)thio]propyl}acetamide

5-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(51 mg) and triethylamine (100 μl) were dissolved in dichloromethane (2ml) and acetyl chloride (25 μl) was added. The reaction was stirredovernight, then water was added and the phases were separated. Theaqueous phase was extracted with dichloromethane, then the organicphases were combined, dried, filtered and evaporated. Purification byHPLC (ethanol:dichloromethane 1-10 :99-90) gave the title compound (36mg).

m.p. 114-117°

MS (+ve APCI) 510 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.81 (6H, d), 1.67 (2H, quint), 1.78 (3H, s),1.99-2.11 (1H, m), 2.99 (2H, t), 3.14 (2H, q), 3.25 (3H, s), 3.59 (2H,d), 4.77 (2H, s), 7.41 (1H, d), 7.49 (1H, t), 7.52-7.58 (2H, m),7.84-7.89 (2H, m), 7.95-7.98 (1H, m) and 8.06-8.09 (1H, m).

EXAMPLE 42N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]primidin-5-yl)thio]propyl}-N′,N′-dimethylurea

Prepared from5-[(3-aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(10 mg) and dimethylcarbamoyl chloride (24.8 mg) following the method ofExample 41 to give the title compound (8 mg).

MS (+ve APCI) 539 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.88 (6H, d), 1.89 (2H, quint), 2.10-2.24 (1H, m), 2.94(6H, s), 3.12-3.17 (2H, m), 3.40 (3H, s), 3.51 (2H, q), 3.64 (2H, d),4.78 (2H, s), 5.44 (1H, t), 7.35 (1H, d), 7.44 (1H, t), 7.48-7.53 (2H,m), 7.81 (1H, d), 7.87-7.90 (1H, m) and 8.02-8.05 (1H, m).

EXAMPLE 43N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}-methoxyacetamide

Prepared from5-[(3-aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenySmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg) andmethoxyacetyl chloride (53 mg) following the method of Example 41 togive the title compound (6 mg).

MS (+ve APCI) 540 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.88 (6H, d), 1.90 (2H, quint), 2.10-2.24 (1H, m),3.07-3.14 (2H, m), 3.41 (3H, s), 3.43 (3H, s), 3.52 (2H, q), 3.63 (2H,d), 3.89 (2H, s), 4.78 (2H, s), 7.02 (1H, t), 7.35 (1H, d), 7.44 (1H,t), 7.48-7.54 (2H, m), 7.81 (1H, d), 7.87-7.90 (1H, m) and 8.00-8.04(1H, m).

EXAMPLE 44 MethylN-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}carbamate

Prepared from5-[(3-aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(10 mg) and methyl chloroformate (34 mg) following the method of Example41 to give the title compound (4 mg).

MS (+ve APCI) 526 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.88 (6H, d), 1.87 (2H, quint), 2.10-2.24 (1H, m), 3.08(2H, t), 3.39 (2H, q), 3.43 (3H, s), 3.63 (2H, d), 3.66 (3H, s), 4.77(2H, s), 5.51 (1H, br), 7.34 (1H, d), 7.44 (1H, t), 7.48-7.53 (2H, m),7.82 (1H, d), 7.87-7.90 (1H, m) and 8.01-8.04 (1H, m).

EXAMPLE 45N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}methanesulfonamide

5-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(50 mg) and triethylamine (100 μl) were dissolved in dichloromethane (5ml) and then cooled in ice. Methanesulfonyl chloride (25 μl) was addeddropwise and the solution was stirred for 1 h. Aqueous ammonia (dilute)was added and the phases were separated. The aqueous phase was extractedtwice with dichloromethane, the organic phases were combined, dried,filtered and evaporated. Purification by HPLC (ethyl acetate:isohexane20-100:80-0) followed by trituration with methanol gave the titlecompound (43 mg).

MS (+ve APCI) 546 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.81 (6H, d), 1.76 (2H, quint), 2.00-2.11 (1H, m),2.87 (3H, s), 3.00-3.09 (4H, m), 3.25 (3H, s), 3.59 (2H, d), 4.77 (2H,s), 7.03 (1H, t), 7.41 (1H, d), 7.50 (1H, t), 7.52-7.60 (2H, m), 7.88(1H, d), 7.95-7.98 (1H, m) and 8.07 (1H, d).

EXAMPLE 46N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}trifluoromethanesulfonamide

5-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenlymethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(48 mg) and triethylamine (100 μl) were dissolved in dichloromethane 5ml and then cooled to −78°. Trifluoromethanesulfonic anhydride (50μl) indichloromethane (2 ml) was added dropwise and the solution was stirredfor 5 minutes. Ammonia in ethanol (1M, 0.5 ml) was added and thereaction mixture was allowed to warm to ambient temperature. Water wasadded and the phases were separated. The aqueous phase was extractedtwice with dichloromethane, the organic phases were combined and dried,filtered and evaporated. Purification by HPLC (ethyl acetate:isohexane5-40:95-60) gave the title compound (23 mg).

MS (+ve APCI) 600 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.82 (6H, d), 1.76 (2H, quint), 2.00-2.11 (1H, m),3.03 (2H, t), 3.25 (3H, s), 3.27 (2H, t), 3.60 (2H, d), 4.76 (2H, s),7.39 (1H, d), 7.49 (1H, t), (2H, m), 7.88 (1H, d), 7.96 (1H, d), 8.04(1H, d), 9.36 (1H, s).

EXAMPLE 475-{[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]thio}-3-methyl-1-(2-methylpropyl)6(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

5-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(Example 4, 470 mg), triphenylphosphine (290 mg) and phthalimide (162mg) were dissolved in tetrahydrofuran (7 ml). A solution of diethylazodicarboxylate (170 μl) in tetrahydrofuran (2 ml) was added dropwiseand the mixture was stirred overnight. Water and ether were added andthe phases were separated. The aqueous phase was extracted withdichloromethane twice. The organic extracts were washed with brine,dried, filtered and evaporated. Column chromatography (2:1ether:isohexane) gave a solid which was triturated hot withisohexane:ethyl acetate (4:1) and then recrystallised fromisohexane:ethyl acetate (2:1) to give the title compound (12 mg).

MS (+ve APCI) 598 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.81 (6H, d), 1.87 (2H, quint), 1.98-2.10 (1H, m),3.01 (2H, t), 3.05 (3H, s), 3.57 (2H, d), 3.67 (2H, t), 4.77 (2H, s),7.38 (1H, d), 7.46 (1H, t), 7.49-7.56 (2H, m), 7.82 (4H, s), 7.85 (1H,d), 7.93-7.96 (1H, m) and 8.06-8.09 (1H, m).

EXAMPLE 48N-(2-Hydroxyethyl)-N′-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)]urea

Diphenylphosphoryl azide (0.27 ml) was added to a solution of1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylicacid (Example 16, step a), 400 mg) and triethylamine (0.18 ml) inanhydrous toluene (12 ml). The mixture was heated at 90° C., undernitrogen for 3 hours, then cooled to room temperature to give a 0.088Msolution ofN-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-y]isocyanate.Some of this solution (3 ml) was treated with ethanolamine (0.019 ml)and after 1 hour, 1M hydrochloric acid (50 ml) was added. Methanol (20ml) was added and the mixture was extracted with ethyl acetate (5×100ml). The combined organic extracts were washed with water (50 ml) thenwith saturated sodium hydrogen carbonate solution (50 ml), dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure to a volume of about 30 ml. After 16 hours, the precipitatedsolid was collected by filtration and dried in vacuo to give the titlecompound (0.058 g).

m.p. 227-228° C.

MS (+ve APCI) 481 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.77 (6H, d), 1.97-2.07 (1H, m), 3.19 (2H, q), 3.21(3H, s), 3.46 (2H, q), 3.51 (2H, d), 4.43 (2H, s), 4.72 (1H, t), 7.01(1H, t), 7.45-7.54 (4H, m), 7.86 (1H, dd), 7.92-7.95 (1H, m), 8.01-8.04(1H, m), 8.26 (1H, s).

EXAMPLE 49 2-Hydroxyethyl[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbamate

Ethylene glycol (1 ml) was added to a 0.088M solution ofN-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]isocyanatein toluene (Example 48, 3 ml). The mixture was heated at 90° C. for 1hour then added to 1M hydrochloric acid (50 ml) and extracted with ether(100 ml). The organic extracts were washed with water (50 ml) and thenwith saturated sodium hydrogen carbonate solution (50 ml), then driedover anhydrous magnesium sulfate, filtered and evaporated under reducedpressure The residue was purified by column chromatography over silica,eluting with ether:isohexane (3:2), and then recrystallised from ethylacetate isohexane to give the title compound (0.023 g).

m.p. 201-202° C.

MS (+ve APCI) 482 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.84 (6H, d), 2.06-1.99 (1H, m), 2.27 (1H, t), 3.38 (3H,s), 3.55 (2H, d), 3.87-3.92 (2H, m), 4.33-4.37 (2H, m), 4.57 (2H, s),7.42-7.51 (4H, m) 7.80-7.84 (1H, m), 7.86-7.89 (1H, m), 7.93-7.97 (1H,m), 8.16 (1H, s, br).

EXAMPLE 50N-(2-Hydroxyethyl)-N-methyl-N′-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)]urea

2-(Methylamino)ethanol (0.026 ml) was added to a 0.088M solution ofN-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]isocyanatein toluene (Example 48, 3 ml). After 16 hours, ethyl acetate (50 ml) wasadded and the mixture was washed with 1M hydrochloric acid (50 ml),water (50 ml) and then saturated sodium hydrogen carbonate solution (50ml), then dried over anhydrous magnesium sulfate, filtered andevaporated under reduced pressure. The residue was purified by columnchromatography over silica, eluting with ether, then recrystallised fromethyl acetate:isohexane to give the title compound (0.061 g).

m.p. 151-152° C.

MS (+ve APCI) 495 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.84 (6H, d), 2.08-2.21 (1H, m), 3.18 (3H, s), 3.23(1H,t), 3.37 (3H, s), 3.55-3.60 (4H, m), 3.87 (2H, q), 4.54 (2H, s),7.43-7.49 (4H, m), 7.79-7.82 (1H, m), 7.85 7.88 (1H, m), 7.95-7.99 (1H,m), 8.37 (1H, s).

EXAMPLE 516-[(1-Hydroxy-1-(3-fluorophenyl))methyl]-3-methyl-1l-(2-methylpropyl)thieno[2,3-d]pyrimiidine-2,4-(1H,3H)-dione

a) 6-Chloro-3-methyl-1-(2-methylpropyl)-1H-pyrimidine-2,4(1H,3H)-dione

A mixture of 6-chloro-3-methyl-1H-pyrimidine-2,4(1H,3H)-dione (J. Amer.Chem. Soc., 1980, 102, 5036) (27.85 g), 1-iodo-2-methylpropane (21.9 ml)and potassium carbonate (26.36 g) in anhydrous dimethylformamide (I 10ml) was stirred at 90° C., under nitrogen for 40 hours. The reactionmixture was cooled to room temperature and diluted with water (800 ml).Brine (100 ml) was added and the mixture was extracted with ether (2×500ml). The organic extracts were dried over anhydrous magnesium sulfate,filtered and evaporated under reduced pressure. The residual oil wastriturated with ether and the resulting crystals were filtered, washedwith ether and dried in vacuo to give the subtitle compound (7.38 g).The mother liquors were evaporated under reduced pressure and purifiedby column chromatography over silica eluting with isohexane:ether (1:1)to give further subtitle compound (6.90 g).

¹H NMR (CDCl₃) δ0.96 (6H, d), 2.10-2.24 (1H, m), 3.34 (3H, s), 3.90 (2H,d), 5.92 (1H, s).

b) 3-Methyl-1-(2-methylpropyl)-6-thioxo-pyrimidine-2,4(1H,3H)-dione

To a stirred solution of6-chloro-3-methyl-1-(2-methylpropyl)-1H-pyrimidine-2,4(1H,3H)-dione(31.5 g) in ethanol (120 ml) was added sodium hydrogen sulfide hydrate(11.83 g). After 16 hours, further sodium hydrogen sulfide hydrate (5.92g) was added and stirring was continued for 5 hours. The reactionmixture was diluted with water and was then extracted with ethyl acetate(2×200 ml). The aqueous layer was acidified by addition of concentratedhydrochloric acid and extracted with ethyl acetate (3×500 ml). Thecombined organic extracts were dried over anhydrous magnesium sulfate,filtered and evaporated under reduced pressure to give the subtitlecompound as a solid (25.44 g).

MS (+ve APCI) 215 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.94 (6H, d) 2.23-2.38 (1H, m), 3.32 (3H, s), 4.16 (2H,s), 4.30 (2H, d).

c) 3-Methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione

Sodium acetate (38.9 g) was added to a stirred suspension of3-methyl-1-(2-methylpropyl)-6-thioxo-pyrimidine-2,4(1H,3H)-dione (25.42g) in water (1 l). After 5 hours, the mixture was filtered. Aqueouschloroacetaldehyde solution (50 wt. %, 142 ml) was added to the filtrateand the mixture was stirred for 16 hours. The mixture was acidified withconcentrated hydrochloric acid and extracted with ethyl acetate (3×500ml). The combined organic extracts were washed with saturated sodiumhydrogen carbonate solution, dried over anhydrous magnesium sulfate,filtered and evaporated under reduced pressure. The residual oil waspurified by column chromatography over silica, eluting withisohexane:ether (1:1) to give the title compound (26.78 g) as a solid.

MS (+ve APCI) 239 ((M+H)⁺).

¹H NMR (CDCl₃) δ1.00 (6H, d), 2.26-2.42 (1H, m), 3.43 (3H, s), 3.81 (2H,d), 6.84 (1h, d), 7.36 (1H, d).

d)6-[(1-Hydroxy-1-(3-fluorophenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione

To a solution of3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (1 g)in tetrahydrofuran (20 ml) at −78° C. was added lithium diisopropylamide(1M, 6.3 ml). After 5 minutes a solution of m-fluorobenzaldehyde intetrahydrofuran (2 ml) was added and the reaction was stirred for 2 h at−78° C. Water (10 ml) was added and the reaction was allowed to warm toroom temperature, then extracted with ethyl acetate. The organic layerwas separated, dried over magnesium sulfate and concentrated in vacuo.The resultant oil was chromatographed (silica), eluting with 1:1isohexane:ethyl acetate to give the title compound (461 mg).

m.p. 54° C.

MS(+ve APCI) 363(M+H)

¹H NMR (DMSO d₆) δ0.90 (6H, d), 2.17 (1H, m), 3.22 (3H, s), 3.60-3.78(2H, dm), 5.98 (1H, d), 6.66 (1H, d), 7.03 (1H, s), 7.11 (1H, m), 7.28(2H, m), 7.41 (1H, m)

EXAMPLE 526-[(3-Fluorophenyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione

To a solution of6-(1-hydroxy-(3-fluoropheyl)methyl-3-methyl-1-(2-methylpropyl)thieno-[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Example 51) (957 mg) in trifluoroacetic acid (7 ml) was addedtriethylsilane (4 ml) and the reaction was allowed to stir for 16 h. Themixture was then poured onto 10% sodium hydroxide and extracted withethyl acetate. The organic layer was dried over magnesium sulfate andthen concentrated in vacuo to a viscous oil. The oil was purified bynormal phase HPLC to give the title compound (82 mg).

m.p. 76-8° C.

MS(+ve APCI) 347(M+H)

¹H NMR (DMSO-d₆) δ0.88 (6H, d), 2.16 (1H, m), 3.23 (3H, s), 3.67 (2H,d), 4.16 (2H, s), 7.04-7.18 (4H, m), 7.37 (H, m).

The following compounds were prepared from3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione andthe appropriate aldehyde following the method of Example 51:

MS m.p./ (+ve APCI) Example Compound ° C. ((M + H)⁺) ¹H NMR (DMSO d₆) δ53 6-[(1-Hydroxy-1-(2-bromo- 143- 424 0.90 (6H, d), 2.18 (1H, m), 3.21(3H, phenyl))methyl]-3-methyl-1- 145 s), 3.70 (2H, m), 6.10 (1H, d),6.69 (2-methylpropyl)thieno[2,3-d]- (1H, d), 6.82 (1H, s), 7.28 (1H, t),pyrimidine-2,4(1H, 3H)-dione 7.48 (1H, t), 7.62 (1H, d), 7.69 (1H, d)

54 6-[(1-Hydroxy-1-(2-methyl- 159- 359 0.90 (6H, d), 2.18 (1H, m), 2.26(3H, phenyl))methyl]-3-methyl-1- 162 s), 3.21 (3H, s), 3.71 (2H, m),6.02 (2-methylpropyl)thieno[2,3-d] (1H, d), 6.35 (1H, d), 6.78 (1H, s)pyrimidine-2,4(1H, 3H)-dione 7.15-7.28 (3H, m), 7.52 (1H, d)

55 6-[(1-Hydroxy-1-(3-cyano- 73- MS (−ve 0.90 (6H, d), 2.18 (1H, m),3.22 (3H, phenyl))methyl]-3-methyl-1- 75 APCI) 368 s), 3.61-3.79 (2H,m), 6.03 (1H, d), (2-methylpropyl)thieno[2,3- (M − H) 6.77 (1H, d), 7.06(1H, s), 7.59 (1H, d]pyrimidine-2,4(1H, 3H)-dione t), 7.78 (2H, m), 7.89(1H, s)

56 6-[(1-Hydroxy-1-(3-trifluoro- 57- MS (+ve 0.90 (6H, d), 2.17 (1H, m),3.21 (3H, methylphenyl))methyl]-3- 60 APCI) 394 s), 3.63-3.79 (2H, m),6.08 (1H, d), methyl-1-(2-methylpropyl)- (M + H) − 6.75 (1H, d), 7.04(1H, s), 7.64 (2H, thieno[2,3-d]-pyrimidine-2,4- H₂O)⁺ m), 7.77 (2H, m)(1H, 3H)-dione

57 6-[(1-Hydroxy-1-(3-phenoxy- 168- 437 0.89 (6H, d), 2.15 (1H, m), 3.22(3H, phenyl))-methyl]-3-methyl-1- 171 s), 3.62-3.78 (2H, m), 5.93 (1H,d), (2-methylpropyl)-thieno[2,3- 6.54 (1H, d), 6.92 (1H, dd), 7.00d]-pyrimidine-2,4(1H, 3H)-dione (3H, m), 7.10-7.22 (3H, m), 7.35- 7.42(3H, m)

58 6-[(1-Hydroxy-1-(1- 174- 395 0.97 (6H, d); 2.3 (1H, m); 2.75 (1H,naphthalenyl))methyl]-3-methyl- 5 d); 3.40 (3H, s); 3.75 (2H, dq); 6.651-(2-methylpropyl)thieno[2,3- (1H, d); 7.00 (1H, s); 7.45-7.60 (3H,d]pyrimidine-2,4(1H, 3H)-dione m); 7.80 (1H, d); 7.85-7.95 (2H, m); 8.03(1H, dd)

59 6-[(1-Hydroxy-1-(6-quinolinyl))- foam 396 (CDCl₃) 0.95 (6H, d), 2.29(1H, m), methyl]-3-methyl-1-(2-methyl- 3.39 (3H, s), 3.6-3.8 (2H, m),6.18 propyl)thieno[2,3-d]pyrimidine- (1H, s), 7.10 (1H, s), 7.45 (1H,dd), 2,4(1H, 3H)-dione 7.74 (1H, dd), 7.93 (1H, s), 8.11 (1H, d), 8.18(1H, d), 8.92 (1H, dd).

60 6-[(1-Hydroxy-1-(4-quinolinyl))- foam 396 (CDCl₃) 0.95 (6H, d), 2.26(1H, m), methyl]-3-methyl-1-(2-methyl- 3.36 (3H, s), 3.6-3.8 (2H, m),6.65 propyl)thieno[2,3-d]pyrimidine- (1H, s), 7.05 (1H, s), 7.54 (1H,t), 2,4(1H, 3H)-dione 7.70 (1H, t), 7.76 (1H, d), 7.94 (1H, d), 8.15(1H, d), 8.97 (1H, d).

61 (±) 6-[1-(Benzo[b]furan-2-yl)-1- 385 hydroxymethyl]-3-methyl-1-(2-methylpropyl))thieno[2,3-d]- pyrimidine-2,4(1H, 3H)-dione

62 6-[(1-Hydroxy-1-(2-chloro-6- 68.9- 397/399 0.92 (6H, d), 2.23 (1H,m), 3.21 (3H, fluorophenyl))methyl]-3-methyl- 70 s), 3.74 (2H, m), 6.38(1H, d), 6.72 1-(2-methylpropyl)thieno[2,3- (1H, s), 6.78 (1H, d), 7.25(1H, dt), d]pyrimidine-2,4(1H, 3H)-dione 7.35-7.47 (2H, m)

63 6-[(1-Hydroxy-1-phenyl)ethyl]- 62- 359 0.89 (6H, m), 1.89 (3H, s),2.16 (1H, 3-methyl-1-(2-methylpropyl)- 64 m), 3.22 (3H, s), 3.58-3.78(2H, dq), thieno[2,3-d]pyrimidine-2,4- 6.45 (1H, s), 7.07 (1H, s), 7.23(1H, (1H, 3H)-dione t), 7.32 (2H, t), 7.51 (2H, d).

64 6-[(1-Hydroxy-1-(4-trifluoro- 152- 413 0.89 (6H, d), 2.17 (1H, m),3.22 (3H, methylphenyl))methyl]-3- 4 s), 3.61-3.79 (2H, m), 6.07 (1H,d), methyl-1-(2-methylpropyl)- 6.73 (1H, d), 7.06 (1H, s), 7.61 (2H,thieno[2,3-d]pyrimidine-2,4(1H, d), 7.61 (2H, d) 3H)-dione

65 (±) 6-(2,3-dihydro-1-hydroxy- 371 1H-indenyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]- pyrimidine-2,4(1H, 3H)-dione

66 6-[(1-Hydroxy-1-(2-quinolinyl))- 396 0.90 (6H, d), 2.20 (1H, m), 3.20(3H, methyl]-3-methyl-1-(2-methyl- s), 3.65-3.75 (2H, m), 6.10 (1H, d),propyl)thieno[2,3-d]pyrimidine- 6.87 (1H, d), 7.05 (1H, s), 7.60 (1H,2,4(1H, 3H)-dione t), 7.7-7.8 (2H, m), 8.00 (2H, t), 8.43 (1H, d).

67 6-[(1-Hydroxy-1-(3-quinolinyl))- foam 396 (CDCl₃) 0.95 (6H, d), 2.28(1H, m), methyl]-3-methyl-1-(2-methyl- 3.39 (3H, s), 3.43 (1H, brs),3.7-3.8 propyl)thieno[2,3-d]pyrimidine- (2H, m), 6.21 (1H, brs), 7.13(1H, s), 2,4(1H, 3H)-dione 7.59 (1H, t), 7.74 (1H, dt), 7.84 (1H, d),8.12 (1H, d), 8.24 (1H, d), 8.92 (1H, d).

The following compounds were made from the corresponding alcohols(above) by the method of Example 52:

MS m.p./ (+ve APCI) Example Compound ° C. ((M + H)⁺) ¹H NMR (DMSO d₆) δ68 6-(2-bromophenylmethyl)-3- 102- 407/409 0.66 (6H, d), 2.16 (1H, m),3.22 (3H, methyl-1-(2-methylpropyl)- 106 s), 3.67 (2H, d), 4.24 (2H, s),6.99 thieno[2,3-d]pyrimidine-2,4(1H, (1H, s), 7.23 (1H, t), 7.39 (1H,t), 3H)-dione 7.48 (1H, d), 7.64 (1H, d)

69 6-(2-methylphenylmethyl)-3- oil 343 0.87 (6H, d), 2.15 (1H, m), 2.26(3H, methyl-1-(2-methylpropyl)- s), 3.14 (3H, s), 3.66 (2H, d), 4.12thieno[2,3-d]pyrimidine-2,4(1H, (2H, s), 6.92 (H, s), 7.16-7.24 (4H,3H)-dione m)

70 6-(3-cyanophenylmethyl)-3- 112- 354 0.88 (6H, d), 2.16 (1H, m), 3.23(3H, methyl-1-(2-methylpropyl)- 113 s), 3.67 (2H, d), 4.21 (2H, s), 7.13thieno[2,3-d]pyrimidine-2,4(1H, (1H, s), 7.55 (1H, t), 7.66-7.44 (2H,3H)-dione m), 7.81 (1H, s)

71 6-(3-trifluoromethylphenyl- 119 397 0.88 (6H, d), 2.16 (1H, m), 3.23(3H, methyl)-3-methyl-1-(2-methyl- s), 3.67 (2H, d), 4.26 (2H, s), 7.13propyl)thieno[2,3-d]- (1H, s), 7.55-7.65 (3H, m), 7.70 (1H,pyrimidine-2,4(1H, 3H)-dione s)

72 6-(3-phenyloxyphenylmethyl)-3- 106 421 0.89 (6H, d), 2.16 (1H, m),3.23 (3H, methyl-1-(2-methylpropyl)- s), 3.68 (2H, d), 4.13 (2H, s),6.87 thieno[2,3-d]pyrimidine-2,4(1H, (1H, dd), 6.98-7.01 (3H, m), 7.07-3H)-dione 7.16 (3H, m), 7.32-7.41 (3H, m)

73 3-Methyl-1-(2-methylpropyl)-6- 198- 380 0.86 (6H, d), 2.15 (1H, m),3.20 (3H, (4-quinolinylmethyl)thieno- 200 s), 3.65 (2H, d), 4.70 (2H,s), 7.17 [2,3-d]pyrimidine-2,4 (1H, 3H)- (1H, s), 7.51 (1H, d), 7.65(1H, t), dione 7.78 (1H, t), 8.05 (1H, d), 8.28 (1H, d), 8.88 (1H, d).

74 3-Methyl-1-(2-methylpropyl)-6- 115- 380 0.86 (6H, d), 2.14 (1H, m),3.23 (3H, (6-quinolinylmethyl)thieno[2,3- 122 s), 3.66 (2H, d), 4.35(2H, s), 7.16 d]pyrimidine-2,4 (1H, 3H)-dione (1H, s), 7.53 (1H, dd),7.70 (1H, dd), 7.88 (1H, d), 7.99 (1H, d), 8.33 (1H, d), 8.88 (1H, dd).

75 3-Methyl-1-(2-methylpropyl)-6- 143- 380 0.88 (6H, d), 2.18 (1H, m),3.22 (3H, (2-quinolinylmethyl)thieno[2,3- 148 s), 3.68 (2H, d), 4.50(2H, s), 7.20 d]pyrimidine-2,4 (1H, 3H)- dec (1H, s), 7.58 (1H, d), 7.61(1H, t), dione, trifluoroacetic acid salt. 7.80 (1H, t), 8.00 (2H, t),8.40 (1H, d).

76 6-(2-Benzo[b]-furanylmethyl)-3- 369 (CDCl₃) 0.97 (6H, d), 2.30 (1H,m), methyl-1-(2-methylpropyl)-)- 3.41 (3H, s),3.74 (2H, d), 4.24 (2H,thieno[2,3-d]-pyrimidine- s), 6.54 (1H, s), 7.10-7.30 (3H, m), 2,4(1H,3H)-dione 7.43 (1H, d), 7.53 (1H, d).

77 6-(2-Chloro-6-fluorophenyl- 122 381/383 0.88 (6H, d), 2.18 (1H, m),3.21 (3H, methyl)-3-methyl-1-(2-methyl- s), 3.67 (2H, d), 4.25 (2H, s),6.94 propyl)thieno[2,3-d]pyrimidine- (1H, s), 7.27-7.33 (1H, m), 7.39(2H, 2,4(1H, 3H)-dione m)

78 6-(1-Phenylethyl)-3-methyl-1- oil 343 0.85 (6H, s), 1.63 (3H, d),2.14 (1H, (2-methylpropyl)thieno[2,3-d]- m), 3.23 (3H, s), 3.56-3.73(2H, m), pyrimidine-2,4(1H, 3H)-dione 4.35 (1H, q), 7.04 (1H, s),7.2-7.37 (5H, m)

79 6-(4-Trifluoromethylphenyl- 121 397 0.88 (6H, d), 2.16 (1H, m), 3.23(3H, methyl)-3-methyl-1-(2-methyl- s), 3.67 (2H, d), 4.25 (2H, s), 7.13propyl)thieno[2,3-d]pyrimidine- (1H, s), 7.53 (2H, d), 7.70 (2H, d)2,4(1H, 3H)-dione

80 (±) 6-(2,3-dihydro-1H-inden-1- 355 (CDCl₃) 0.95 (6H, dd), 2.1-2.2(1H, yl)-3-methyl-1-(2-methyl- m), 2.2-2.3 (1H, m), 2.6-2.7 (1H,propyl)thieno[2,3-d]pyrimidine- m), 2.9-3.1 (2H, m), 3.42 (3H, s),2,4(1H, 3H)-dione 3.6-3.8 (2H, dq), 4.55 (1H, t), 7.1- 7.3 (5H, m).

EXAMPLE 816-(3-Imino-1,3-dihydro-benzo[c]furan-1-yl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a solution of3methyl-1-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (500m) intetrahydrofuran (10 ml) at −78° C. was added lithium diisopropylamide(1M, 3.1 ml). After 5 minutes a solution of o-cyanobenzaldehyde intetrahydrofuran (2 ml) was added and the reaction was allowed to stirfor 2 h. Water (10 ml) was the added and the mixture was allowed to warmto room temperature. The mixture was extracted with ethyl acetate. Theorganic layer was separated and dried over magnesium sulfate, thenconcentrated in vacuo and purified by normal phase HPLC to yield thetitle compound (15 mg).

m.p. 152° C.

MS(+ve APCI) 370(M+H)

EXAMPLE 822-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl)methyl]benzamido

Prepared form6-(3-Imino-1,3-dihydro-benzo[c]furan-1-yl)-3-methyl-1-(2-methylpropy)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione following the method of Example 52.

m.p. 183° C.

MS(+ve APCI) 372 (M+H)

¹H NMR DMSO-d₆ δ0.88(6H, d), 2.16 (1H, m), 3.32 (3H, s), 3.65 (2,H, d)4.31 (2H, s), 7.03 (1H, s), 7.27-7.49 (5H, m), 7.88 (1H, bs).

EXAMPLE 83 (±)6-(1-Hydroxy-1-[1-naphthalenyl]methyl)-5-([3-hydroxypropyl]thio)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

a) (±)6-(1-[Dimethy-(1,1-dimethylethyl)silyloxyl-]1-[1-naphthalenyl]methyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione

Dimethyl-(1,1-dimethylethyl)silyl chloride (230 mg) and imidazole (130mg) were added to a solution of(±)6-(1-hydroxy-1-[1-naphthalenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione(500 mg) in dimethylformamide (10 ml). The solution was stirred atambient temperature for 3 days. The reaction mixture was quenched withdilute hydrochloric acid and extracted with ethyl acetate. The organicphase was separated and washed twice with dilute hydrochloric acid andonce with brine, dried over magnesium sulfate and concentrated in vacuo.Purification by chromatography on silica gel eluting withisohexane:ethyl acetate (4:1 to 2:1) gave the subtitle product (0.47 g).

MS (APCI) 509 ((M+H)⁺)

b)(±)6-(1-Hydroxy-1-[1-naphthalenyl]methyl)-5-([3-hydroxypropyl]thio)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

A solution of lithium diisopropylamide (1.40 mmol) in tetrahydrofuran (5ml) was added to a solution of(±)6-(1-[dimethyl-1,1-dimethylethylsilyloxy]-1-[1-naphthalenyl]methyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(450 mg) and 3-{[dimethyl-(1,1-dimethylethyl)silyl]oxy}propyl4-methylphenylthiosulfonate (J. Med. Chem. 1995, 38, 2557, 500 mg) intetrahydrofuran (15 ml) at −78° C. After 1 h at −78° C. the reactionmixture was allowed to warm to ambient temperature. The reaction mixturewas quenched with dilute hydrochloric acid and extracted with ethylacetate. The organic phase was separated and washed twice with dilutehydrochloric acid, twice with saturated sodium hydrogen carbonatesolution and once with brine, then dried over magnesium sulfate andconcentrated in vacuo. The residue was dissolved in acetonitrile (3 ml)and hydrofluoric acid (40%aqueous, 0.1 ml) was added. After 24 h thereaction mixture was quenched by the addition of saturated sodiumhydrogen carbonate solution and extracted into ethyl acetate. Theorganic phase was separated and washed twice with saturated sodiumhydrogen carbonate solution and once with brine, dried over magnesiumsulfate and concentrated in vacuo. Purification by chromatography onsilica gel eluting with ethyl acetate gave the title compound (0.012 g).

m.p. 100-105° C.

MS (APCI) 467 ((M+H−H₂O)⁺)

¹H NMR (DMSO d₆) δ0.3 (6H, t); 1.58 (2H, quin); 2.10 (1H, m); 2.87 (1H,m); 2.95 (1H, m); 3.24 (3H, s); 3.30 (2H, dt); 3.50 (1H, dd); 3.70 (1H,dd); 4.41 (1H, t); 7.14 (1H,); 7.38 (1H, ); 7.49 (1H, t); 7.55-7.65 (2H,m); 7.93 (1H, d); 8.00-8.05 (2H, m).

EXAMPLE 843-Methyl-1-(2-methylpropyl)-6-(-naphthalenylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

1-Naphthoyl chloride (1.25 ml) was added under nitrogen to a stirredslurry of aluminium chloride (1.1 g) in 1,2-dichloroethane (10 ml). Asolution of3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (2.0g) in 1,2-dichloroethane (10 ml) was added dropwise and the resultantmixture was heated under reflux for 24 h and then allowed to cool toambient temperature. The reaction mixture was quenched by the carefuladdition of water (2 ml) and was then concentrated in vacuo. The residuewas dissolved in ethyl acetate and washed thrice with dilutehydrochloric acid, twice with saturated sodium hydrogen carbonatesolution, and once with brine, then dried over magnesium sulfate andconcentrated in vacuo. Purification by chromatography on silica geleluting with toluene:ethyl acetate (9:1) gave the title compound (0.78g).

m.p. ˜150° C.

MS (APCI) 393 ((M+H)⁺)

¹H NMR (DMSO d₆) δ1.00 (6H, d); 2.25 (1H, m); 3.22 (3H,s); 3.80 (2H, d);7.47 (1H, s); 7.55-7.65 (2H, m); 7.70 (1H, t); 7.85 (1H, d); 8.05 (1H,dd); 8.10 (1H, dd); 8.20 (1H, d).

EXAMPLE 85(±)-5-[(3-Hydroxybutyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno2,3-d]pyrimidine-2,4(1H,3H)-dione

A solution of dimethylsulfoxide (0.113 ml) in anhydrous dichloromethane(1 ml) was added to a solution of oxalyl chloride (0.093 ml) inanhydrous dichloromethane (5 ml) at −78° C. under nitrogen. After 5minutes, a solution of5-[(3-hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(0.25 g) in anhydrous dichloromethane (4 ml) was added dropwise. After10 minutes, triethylamine (0.372 ml) was added and the mixture waswarmed to room temperature. Ether (30 ml) was added and the mixture waswashed with 2M hydrochloric acid (10 ml) then with saturated sodiumhydrogen carbonate solution (10 ml), then dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was dissolved in anhydroustetrahydrofuran (10 ml), cooled to −78° C. under nitrogen and treatedwith methyl magnesium chloride (3.0M solution in tetrahydrofuran, 0.265ml). The mixture was warmed to room temperature, then added to saturatedsodium hydrogen carbonate solution (30 ml) and then extracted with ethylacetate (2×30 ml). The organic extracts were dried over anhydrousmagnesium sulfate, filtered through a small silica pad and evaporated.The residue was purified by preparative normal-phase HPLC with ethylacetate/isohexane gradient elution followed by recrystallisation fromethyl acetate/isohexane to give the title compound (58 mg).

m.p. 162-163° C.

MS (+ve APCI) 483 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.88 (6H, d), 1.25 (3H, d), 1.76-1.82 (2H, m), 2.10-2.25(1H, m) 3.10-3.23 (3H, m), 3.42 (3H, s), 3.57-3.75 (2H, m), 4.14-4.26(1H, m), 4.77 (2H, ABq), 7.35 (1H, d), 7.45 (1H, t), 7.50-7.56 (2H, m),7.82 (1H, d), 7.87-7.90 (1H, m), 8.02-8.06 (1H, m).

EXAMPLE 866-(3-Fluorophenyl)methyl-5-[(3-hydroxypropyl)thio]-3-methyl-1-(2-methylpropythieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

A tetrahydrofuran solution of lithium diisopropylamide (5.0 ml, 0.72mmol) was added to a solution of6-(3-fluorophenyl)methyl-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione(Example 52, 0.24 g) in anhydrous tetrahydrofuran (5 ml), at −78° C.under nitrogen. After 15 minutes, further lithium diisopropylamidesolution (2.5 ml, 0.36 mmol) was added. The reaction mixture wasmaintained at −78° C. for a further 3 hours.3-{[Dimethyl-(1,1-dimethylethyl)silyl]oxy}propyl4-methylphenylthiosulfonate (J. Med. Chem. 1995, 38, 2557., 0.286 g) wasadded and the mixture was heated at 50° C. for 30 minutes. The reactionmixture was added to saturated sodium hydrogen carbonate solution (50ml) and extracted with ether (50 ml). The organic extracts were driedover anhydrous magnesium sulfate, filtered and evaporated. The residuewas dissolved in acetonitrile (10 ml) and then treated with 40%hydrofluoric acid (1 ml). After 1 hour, the mixture was added tosaturated sodium hydrogen carbonate solution (100 ml) and extracted withether (2×50 ml). The organic extracts were dried over anhydrousmagnesium sulfate, filtered and evaporated. The residue was purified bycolumn chromatography over silica, eluting with ethyl acetate:isohexane(1:1) followed by recrystallisation from ethyl acetate/isohexane to givethe title compound (0.058 g).

m.p. 99-100° C.

MS (+ve APCI) 437 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.96 (6H, d), 1.84 (2H, quin), 2.19-2.34 (1H, m), 2.76(1H, t), 3.06 (2H, t), 3.43 (3H, s), 3.74 (2H, d), 3.85 (2H, q), 4.32(2H, s), 6.90-7.02 (3H, m), 7.25-7.32 (1H, m).

EXAMPLE 875-[(5-Amino-2-pyridinyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

Iron powder (0.85 g) and ammonium chloride (0.81 g) were added to astirred suspension of3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(5-nitropyridin-2-yl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Example 37, 2.02 g) in ethanol (10 ml) and water (10 ml). Themixture was heated at reflux for 3 hours, then cooled to roomtemperature. 2M Sodium hydroxide solution (50 ml) was added and themixture was stirred vigorously for 1 hour, ethyl acetate (100 ml) wasadded and the two-phase mixture was filtered. The solid and aqueouslayer were in turn washed with ethyl acetate (100 ml). 2M Hydrochloricacid (25 ml) was added to the solid and the mixture was stirred for 1hour, then added to the sodium hydroxide solution and extracted withethyl acetate (2×10 ml). The combined organic extracts were dried overanhydrous magnesium sulfate, filtered and evaporated. The residue wasrecrystallised from ethyl acetate to give the title compound (1.07 g).The mother liquors were evaporated and purified by column chromatographyover silica, eluting with ethyl acetate, and then recrystallised fromethyl acetate to give further title compound (0.665 g).

m.p. 208-209° C.

MS (+ve APCI) 503 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.81 (6H, d), 1.97-2.02 (1H, m), 3.15 (3H, s), 3.58(2H, d), 4.72 (2H, s), 5.26 (2H, s, br), 6.89 (2H, ABq), 7.38 (1H, td),7.45-7.55 (3H, m), 7.83 (1H, t), 7.85-7.90 (1H, m), 7.93 (1H, d), 8.02(1H, d).

EXAMPLE 88 Ethyl1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate

a) Diethyl 2-amino-5-phenylmethylthiophene-3,4-dicarboxylate

Prepared from sulfur (0.85 g), triethylamine (3.69 ml), ethyl2-oxo-4-phenylbutyrate (5.00 ml) and ethyl cyanoacetate (2.81 ml) indimethylformamide (15 ml) following the method of Example 1, step b togive the subtitle compound (4.133 g) as an oil.

MS (+ve APCI) 334 ((M+H)⁺)

¹H NMR (CDCl₃) δ1.30 (3H, t), 1.33 (3H, t), 3.94 (2H, s), 4.24 (2H, q),4.30 (2H, q), 5.88 (2H, s, br), 7.20-7.35 (5H, m).

b) Diethyl2-(2-methylpropyl)amino-5-phenylmethylthiophene-3,4-dicarboxylate

Prepared from sodium borohydride (2.2 g) and diethyl2-amino-5-phenylmethylthiophene-3,4-dicarboxylate (4.10 g) in2-methylpropanoic acid (20 ml) following the method of Example 3 step bto give the subtitle compound (2.39 g) as an oil.

MS (+ve APCI) 390 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.94 (6H, d), 1.29 (3H, t), 1.33 (3H, t), 1.84-1.98 (1H,m), 2.95 (2H, t), 3.94 (2H, s), 4.20 (2H, q), 4.30 (2H, q), 7.19-7.35(5H, m), 7.66 (1H, t, br).

c) Ethyl1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate

Prepared from acetyl chloride (0.60 ml), silver cyanate (1.35 g) anddiethyl2-(2-methylpropyl)amino-5-phenylmethylthiophene-3,4-dicarboxylate (2.38g) following the method of Example 3 step c and treating the residuewith sodium ethoxide (1.24 g) and iodomethane (1.14 ml) in ethanol (24ml) following the method of Example 4 to give the title compound (1.58g).

MS (+ve APCI) 401 ((M+H)⁺)

¹H NMR (CDCl₃) δ0.93 (6H, d), 1.39 (3H, t), 2.17-2.30 (1H, m), 3.39 (3H,s), 3.69 (2H, d), 4.12 (2H, s), 4.44 (2H, q), 7.24-7.36 (5H, m).

EXAMPLE 891,2,3,4-Tetrahydro-3,N,N-trimethyl-1-(2-methylpropyl)-6-phenylmethy-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide

a)1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylicacid

1M Sodium hydroxide solution (7.5 ml) was added to a stirred solution ofethyl1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate(1.50 g) in methanol (7.5 ml) and tetrahydrofuran (15 ml). After 16hours, further 1M sodium hydroxide solution (7.5 ml) was added and thesolution was stirred at 50° C. for a further 8 hours. Water (100 ml) wasadded and the solution was washed with ether (100 ml). The aqueous phasewas acidified by addition of concentrated hydrochloric acid and thenextracted with ethyl acetate (2×100 ml). Undissolved solid in theorganic extracts was filtered and dried in vacuo at 50° C. to give thetitle compound (1.00 g).

m.p. 238° C. (dec)

MS (+ve APCI) 373 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.87 (6H, d), 2.05-2.20 (I H, m), 3.25 (3H, s), 3.68(2H, d), 4.25 (2H, s), 7.24-7.36 (5H, m), 13.92 (1H, s, br).

b)1,2,3,4-Tetrahydro-3,N,N-trimethyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide

Oxalyl chloride (0.087 ml) was added to a stirred solution of1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylicacid (0.37 g) and dimethylformamide (0.01 ml) in anhydrousdichloromethane (20 ml). After 1 hour, the solution was evaporated. Theresidue was dissolved in anhydrous tetrahydrofuran (7 ml) and 1 ml ofthis solution was added to a stirred mixture of 40% aqueousdimethylamine solution (1 ml) and saturated sodium hydrogen carbonatesolution (2 ml). After 30 minutes water (10 ml) was added and themixture was extracted with ethyl acetate (10 ml). The organic extractswere dried over anhydrous magnesium sulfate, filtered and evaporated.The residue was recrystallised from ethyl acetate/isohexane to give thetitle compound (0.025 g).

m.p. 144-146 C

MS (+ve APCI) 400 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.89 (6H, d), 2.08-2.21 (1H, m), 2.64 (3H, s), 2.97(3H, s), 3.21 (3H, s), 3.59-3.76 (2H, m), 3.97 (2H, ABq)7.21-7.35 (5H,m).

EXAMPLE 906-[1-Hydroxy-(4-nitrophenyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione

Prepared from3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione(Example 51, step c) and 4-nitrobenzaldehyde following the method ofExample 51, step d.

m.p. 156° C.

¹H NMR (DMSO d₆) δ0.89 (6H, d), 2.17 (1H, m), 3.21 (3H, s), 3.61-3.79(2H, m), 6.14 (1H, d), 6.84 (1H, d), 7.10 (1H, s), 7.73 (2H, d), 8.24(2H, d).

EXAMPLE 916-(4-Nitrophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione

Prepared from6-[1-Hydroxy-(4-nitrophenyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione following the method of Example 52.

m.p. 127° C.

MS (+ve APCI) 372 ((M−H)⁻)

¹H NMR (DMSO d₆) δ0.88 (6H, d), 2.18 (1H, m), 3.23 (3H, s), 3.67 (2H,d), 4.31 (2H, s), 7.15 (1H, s), 7.59 (2H, d), 8.20 (2H, d).

EXAMPLE 926-(4-Aminophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione

To a solution of6-(4-nitrophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (275 mg) in ethanol (15 ml) and water (1 ml) was added ironpowder (82 mg) and ammonium chloride (78 mg). The mixture was heated at90° C. for 6 h. and then allowed to cool to room temperature. Thereaction was filtered and then evaporated before being partitionedbetween ethyl acetate and water. The organic layer was collected, driedover magnesium sulfate, and then evaporated. The resultant oil waspurified by normal phase HPLC (isohexane:ethyl acetate 80-0:20-100) togive the title compound (20 mg).

m.p. 104° C.

MS (+ve APCI) 344 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.87 (6H, d), 2.15 (1H, m), 3.22 (3H, s), 3.66 (2H,d), 3.91 (2H, t), 4.98 (2H, s), 6.51 (2H, d), 6.91 (1H, s), 6.94 (2H,d).

EXAMPLE 934-(3,4-Dimethoxyphenyl)-N-{4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl)methyl]phenyl}-butanamide

To a solution of N-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide (37mg), 1-hydroxybenzotriazole (26 mg) and4-(3,4-dimethyloxyphenyl)butanoic acid (36 mg) in dichloromethane (6 ml)was added6-(4-aminophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (45 mg) in dichloromethane (2 ml). The reaction mixture wasstirred overnight and then washed with half saturated sodium hydrogencarbonate and extracted into ethyl acetate. The organic layer was driedover magnesium sulfate, evaporated and the residue was purified bynormal phase HPLC (isohexane:ethyl acetate 50-0:50-100) to give thetitle compound (19 mg) as a foam.

MS (+ve APCI) 550 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.87 (6H, d), 1.88 (2H, m), 2.01(1H, m), 2.29(2H, t),2.51(2H, t), 3.32 (3H, s), 3.66 (2H, d), 3.73 (3H, s), 3.75 (3H, s),4.06 (2H, s), 6.70 (1H, m), 6.72 (1H, m), 6.84 (1H, m), 7.03 (1H, s),7.19 (2H, d), 7.53 (2H, d), 9.85 (1H, s).

EXAMPLE 943-Acetamido-N-(4-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl)methyl]phenyl)benzamide

Prepared following the method of Example 93 from6-(4-aminophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione and 3-acetamidobenzoic acid.

m.p. 230° C.

MS (+ve APCI) 505 ((M+H)⁺)

¹H NMR (DMSO d₆) δ0.88 (6H, d), 2.19 (1H, m), 3.23 (3H, s), 3.32 (3H,s), 3.67 (2H, d), 4.10 (2H, s), 7.06 (1H, s), 7.23 (2H, d), 7.43 (1H,t), 7.59 (1H, d), 7.71 (2H, d), 7.81 (1H, d), 8.06 (1H, s), 10.13 (1H,s), 10.24 (1H, s).

EXAMPLE 95 Inhibition of Human Mixed Lymphocyte Reaction (MLR)

The MLR test was performed in 96-well flat bottomed microtitre plates.Compounds were prepared as 10 nM stock solution in dimethyl sulphoxide.A 50 fold dilution of this was prepared in RPMI. Serial dilutions wereprepared from this solution. 10 μl of the 50 fold diluted stock, ordilutions of it, were added to the well to give concentrations in theassay starting at 9.5 μm and going down. Into each well was placed1.5×10⁵ cells from each of two responding donors in a final volume of0.2 ml RPMI 1640 medium supplemented with 10% human serum, 2 mML-glutamine and penicillin/streptomycin. The cells were incubated at 37° C. in a humidified atmosphere at 5% carbon dioxide for 120 hours.³H-Thymidine (0.5 μCi) was added for the final 6 hours of theincubation. The level of radioactivity incorporated by the cells wasthen determined, which is a measure of T-cell proliferation. The titlecompounds of Examples 1 to 94 were found to exhibit an IA₅₀ value ofless than 1×10⁻⁶ M in the above test.

What is claimed is:
 1. A method of treating, or reducing the risk of,asthma in a patient suffering from, or at risk of, said disease, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of formula (I):

wherein: R is —C(O)Ar¹, —C(R⁴)(R⁵)Ar¹, or Ar²; Ar¹ is naphthyl,quinolyl, isoquinolyl, indolyl, benzofuranyl or benzothienyl, each ofwhich can be optionally substituted by one or more substituents selectedfrom C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or trifluoromethyl, or Ar¹ isphenyl optionally substituted by one or more substituents selected fromC₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, trifluoromethyl, amino, nitro, cyano,trifluoromethoxy, phenoxy, —CH₂N(R⁶)₂, —NHSO₂CF₃, C₁₋₄alkylsulphonylamino, —NHC(O)R^(6a), CO₂R⁷ or —C(O)NR⁸R^(8a); R⁴represents H or C₁₋₄ alkyl; R⁵ represents H or OH; each R⁶ independentlyrepresents H or C₁₋₄ alkyl; R^(6a) represents H, C₁₋₆ alkyl, aryl orarC₁₋₄ alkyl, wherein the aryl group or aryl moiety in the aralkyl groupis phenyl or pyridyl, each of which may be optionally substituted by oneor more substituents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylcarbonylamino, halogen or trifluoromethyl; R⁷ represents H or C₁₋₄alkyl; R⁸ and R^(8a) each independently represent H, C₁₋₄ alkyl, phenylor pyridyl; Ar² is acenaphthenyl, indanyl, iminodihydrobenzofuranyl orfluorenyl, each of which can be optionally substituted by one or moresubstituents selected from OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, ortrifluoromethyl; R¹ and R² are independently H, C₁₋₆ alkyl, C₃₋₆alkenyl, CH₂CH₃₋₅ cycloalkyl or C₃₋₆ cycloalkyl; R³ represents H, X—R⁹or X—Ar³; X represents S(O)_(n), C(O)NR¹⁰, C(O)O, NH(CO)NR¹⁰, NH(CO)O orSO₂NR¹⁰; n is 0, 1 or 2; R⁹ represents a methyl group optionallysubstituted by one or more substituents selected from CN, CO₂H, C₁₋₅alkoxycarbonyl, 5-tetrazolyl, SO₂NH₂ or C(O)NR¹¹R¹², or represents C₂₋₆alkyl or C₃₋₆ alkenyl, each of which may be optionally substituted byone or more substituents selected from OH, CN, CO₂H, C₁₋₅ alkoxy, C₁₋₅alkoxycarbonyl, 5-tetrazolyl, azide, phthalimido, SO₂NH₂, C(O)NR¹¹R¹²,NR¹³R¹⁴, NHC(O)R¹⁵ or NHSO₂R¹⁶ where R¹¹, R¹², R¹³ and R¹⁴ eachindependently represent H or C₁₋₄ alkyl, R¹⁵ represents C₁₋₄ alkyl, C₁₋₄alkoxy, di(C₁₋₄alkyl)amino, or alkoxyalkylene containing up to 6 carbonatoms, and R¹⁶ represents C₁₋₄ alkyl or trifluoromethyl; or,additionally, in the case where X represents C(O)NR¹⁰, NH(CO)NR¹⁰ orSO₂NR¹⁰, R⁹ and R¹⁰ together with the nitrogen atom to which they areattached may form a 4- to 7-membered heterocyclic ring which may beoptionally substituted by one or more OH groups; R¹⁰ represents H, C₁₋₆alkyl or is linked to as defined above; and Ar³ is phenyl, pyridyl orpyridine N-oxide, each of which may be optionally substituted by one ormore substituents selected from OH, NO₂, NH₂, NHSO₂CF₃, C₁₋₄ alkoxy, bisC₁₋₄ alkanesulphonylamino, C₁₋₄ alkylcarbonylamino oralkoxycarbonylamino; or a pharmaceutically-acceptable salt or solvatethereof.
 2. A method according to claim 1 wherein Ar¹ is naphthyl,quinolyl or benzofuranyl, or a phenyl group optionally substituted byone or two substituents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen,trifluoromethyl, nitro, amino, cyano, phenoxy or —NHC(O)R^(6a).
 3. Amethod according to claim 1 wherein R⁴ represents H, methyl or ethyl. 4.A method according to claim 1 wherein Ar² is indanyl,iminodihydrobenzofuranyl or hydroxy-substituted indanyl.
 5. A methodaccording to claim 1 wherein R¹ and R² are independently H, C₁₋₄ alkyl,C₃₋₄ alkenyl or C₃₋₆ cycloalkyl.
 6. A method according to claim 1wherein R⁹ represents a methyl group optionally substituted by CO₂H orC(O)NR¹¹R¹², or a C₂₋₄ alkyl group which may be optionally substitutedby one or two substituents selected from OH, CO₂H, C₁₋₅alkoxycarbonyl,azide, phthalimido, NR¹³R^(l4), NHC(O)R¹⁵ or NHSO₂R¹⁶; or R⁹ and R¹⁰together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring which may be optionally substituted by anOH group.
 7. A method according to claim 1 wherein R¹⁰ represents H,methyl, or is linked to R⁹ as defined in claim
 1. 8. A method accordingto claim 1 wherein each of R¹¹, R¹², R¹³ and R¹⁴ represents hydrogen. 9.A method according to claim 1 wherein R¹⁵ represents methyl, methoxy,dimethylamino or methoxymethylene.
 10. A method according to claim 1wherein R¹⁶ represents methyl or trifluoromethyl.
 11. A method accordingto claim 1 wherein Ar³ is phenyl, pyridyl or pyridine N-oxide, each ofwhich may be optionally substituted by one or two substituents selectedfrom OH, NO₂, NH₂, methoxy, bis-methanesulphonylamino,methylcarbonylamino or methoxycarbonylamino.
 12. A method according toclaim 1 wherein the compound of formula (I) is selected from6-(4-Methoxyphenylmethyl)-3methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-(4-Methoxyphenylmethyl)-3-methyl-1-(2-methyl-2-propenyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione,1-(2-Methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrmidine-2,4(1H,3H)-dione,3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(2-pyridinylthio]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,5-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.Methyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropy)-6-(1-naphthalenylmethyl)-2,4dioxothieno[(2,3-d]pyrimidin-5-yl)thio]butanoate,4-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]butanoicacid, Methyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno(2,3-d]pyrimidin-5-yl)sulfinyl]butanoate.13. A method according to claim 1 wherein the compound of formula (I) isselected from Methyl4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)sulfonyl]butanoate,4-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl-)sulfonyl]butanoicacid,6-Benzyl-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pryimidine-2,4(1H,3H)-dione,3-Methyl-1-(1-methylethyl)-6-(phenylmethyl)theino[2,3-d]pyrimidine-2,4-(1H,3H)-dione,6-[(1-Hydroxy-1-phenyl)methyl]-3-methyl-1-(2-methylpropyl)theino[2,3-d]pyrimidine-2,4(1H,3H)-dione,(±)5-[(2-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-3methyl-1-(2-methylpropyl)-6-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pryimidine-5-carboxamide,(3R)-1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl}pyrrolidin-3-ol,1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl}piperidin-4-ol,(3R)-1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[(2,3-d]pyrimidin-5-yl]carbonyl}piperidin-3-ol,1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-3,N-dimethyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide,2-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carboxamido}aceticacid.
 14. A method according to claim 1 wherein the compound of formula(I) is selected from3-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carboxamido}propanoicacid,2-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno([2,3-d]pyrimidin-5-yl]carboxamido}acetamide,1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno(2,3-d]pyrimidin-5-yl]carbonyl}pyrrolidine,1,2,3,4-Tetrehydro-N-(2-hydroxyethyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-sulfonamide,5-[(3-Methoxyphenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidne-2,4-(1H,3H)-dione,5-[(3-Hydroxyphenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,5-[(3-Hydroxyhenyl)sufinyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[(2,3-d]pyrimidine-2,4-(1H,3H,-dione,5-[(3-Hydroxyphenyl)sulfonyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(3-nitrophenyl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,5-[(3-Aaminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethy)thieno[2,3-d]pyrmidine-2,4-(1H,3H)-dione,5-{[3-(Bis-methanesulfonyl)amino}phenyl]thio}-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,5-[(3-Methoxycarbonylaminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,5-[(3-Acetamidophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione.
 15. A method according to claim 1 wherein the compound offormula (I) is selected from3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(4-nitroheyl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione.5-[(4-Aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3d]pyrimidine-2,4-(1H,3H)-dione,3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(5-nitropyridin-2-yl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,2-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]thio}pyridineN-oxide,5-[(3-Azidopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,5-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}acetamide,N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}-N′,N′-dimethylurea,N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}-methoxyacetamide,MethylN-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}carbamate,N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}methanesulfonamide,N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}trifluoromethanesulfonamide,5-{[3-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]thio}-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.16. A method according to claim 1 wherein the compound of formula (I) isselected fromN-(2-Hydroxyethyl)-N′-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]urea,2-Hydroxyethyl[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbamate,N-(2-Hydroxyethyl)-N-methyl-N′-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]urea,6-[(1-Hydroxy-1-(3-fluorophenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,6-[(3-Fluorophenyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,6-[(1-Hydroxy-1-(2-bromophenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione,6-[(1-Hydroxy-1-(2-methylphenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione,6-[(1-Hydroxy-1-(3-cyanophenyl))methyl]-1-(2-methylpropyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione,6-[(1-Hydroxy-1-(3-trifluoromethylphenyl))methyl]-3-methyl-1(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-[(1-Hydroxy-1-(3-phenyloxyphenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-[(1-Hydroxy-1(1-naphthalenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione,6-[(1-Hydroxy-1-(6-quinolinyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione6-[(1-Hydroxy-1-(4-quinolinyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione.17. A method according to claim 1 wherein the compound of formula (I) isselected from (±)6-[1-(Benzo[b]furan-2-yl)-1-hydroxymethyl]-3-methyl-1-(2-methylpropyl))-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-[(1-Hydroxy-1-(2-chloro-6-fluorophenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno-[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-[(1-Hydroxy-1-phenyl)ethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-[(1-Hydroxy-1-(4-trifluoromethylphenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, (±)6-(2,3-dihydro-1-hydroxy-1H-indenyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione,6-[(1-Hydroxy-1-(2-quinolinyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione,6-(1-Hydroxy-1-[3-quinolinyl]methyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione,6-(2-bromophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-(2-methylphenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-(3-cyanophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-(3-trifluoromethylphenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione,6-(3-phenyloxyphenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,3-Methyl-1-(2-methylpropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.18. A method according to claim 1 wherein the compound of formula (I) isselected from3-Methyl-1-(2-methylpropyl)-6-(6-quinolinylmethyl)thieno[2,3-d]pyrmidine-2,4(1H,3H)-dione,3-Methyl-1-(2-methylpropyl)-6-(2-quinolinylmethyl)thieno(2,3-d]pyrimidine-2,4(1H,3H)-dione,trifluoroactic acid salt,6-(2-Benzo[b]furanylmethyl)-3-methyl-1-(2-methylpropyl)-)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-(2-Chloro-6-1-fluorophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-(1-Phenylethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-(4-Trifluoromethylphenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, (±)6-2,3-dihydro-1H-inden-1-yl)-3-methyl-1-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-(3-Imino-1,3-dihydro-benzo[c]furan-1-yl)-3-methyl-1-(2-methylpropyl)thieno-[2,3-d]pyrimidine-2,4(1H,3H)-dione,2-1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-pyrimidin-6-yl)methyl]benzamide,(±)6-(1-Hydroxy-1-[1-naphthalenyl]methyl)-5-([3-hydroxypropyl]thio)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,(±)-5-[3-Hydroxybutyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,6-(3-Fluorophenyl)methyl-5-[(3-hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.19. A method according to claim 1 wherein the compound of formula (I) isselected from5-[(5-Amino-2-pyridinyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno(2,3-d]pyrimidine-2,4(1H,3H)-dione,Ethyl1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate,1,2,3,4-Tetrahydro-3,N,N-trimethyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide,6-[1-Hydroxy-(4-nitrophenyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione,6-(4-Nitrophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione, 6-(4-Aminophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,4-(3,4-Dimethoxyphenyl)-N-{4-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl)methyl]phenyl}-buranamide,and3-Acetamido-N-(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-pyrimidin-6-yl)methyl]phenyl)benzamide.